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The goal of this study was to investigate the value of the long-term average spectrum in the acoustic analysis of snore sounds arising from different sources in the upper airway.Long-term average spectrum was used to analyze sequences of 10 consecutive snore sounds that had been divided into 2 groups, soft-palate type and lateral-wall type, according to the vibration site generating the snore sounds and the patterns of soft tissue collapse in the upper airway as identified by drug-induced sleep endoscopy. We calculated the first spectral peak, mean spectral energy, high-frequency energy, 0-1 kHz spectral energy, 1-5 kHz spectral energy, and 0-1 kHz/1-5 kHz difference from each group and compared the differences between them.All parameters except mean spectral energy showed significant differences between the 2 groups. The first spectral peak of less than 265.53 Hz, and the 0-1k/1-5 kHz difference of less than -11.6 dB strongly suggests soft-palate-type snore sounds.Long-term average spectrum has potential application for snore sound source identification. We recommend using first spectral peak and a 0-1 kHz/1-5 Hz difference to identify soft-palate-type snore sounds.Peng H, Xu H, Xu Z, Jia R, Yu H. Long-term average spectrum measures of consecutive snore sounds from different sources determined by drug-induced sleep endoscopy.

The effect of reductions in homocysteine (Hcy) on cardiovascular disease (CVD) was suggested to be modified by platelet activation, but the interaction between Hcy and platelet activation on CVD events is not well studied. Here, we aimed to examine the interaction between Hcy and platelet activation on CVD in a large, real-world population.A total of 27,234 patients with hypertension (mean 63 years, 48% male) who were registered in Taicang city and free of CVD were prospectively followed up for new CVD events from 2017 to 2020. Hcy and platelet indices including mean platelet volume (MPV) were assayed at baseline. A total of 1063 CVD events were recorded during follow-up. Hcy at baseline was significantly associated with a higher risk of CVD (HR = 1.85, P 0.001 for log-transformed Hcy). MPV showed a significant interaction effect with Hcy on CVD (HR = 1.20, P = 0.030 for the interaction term). The association between Hcy and CVD was significantly stronger in participants with a large (vs. small) MPV (HR = 2.71 vs. 1.32, P = 0.029 for log-transformed Hcy). For participants with both elevated Hcy and a large MPV, the attributable proportion of CVD events due to their interaction was 0.26 (95% CI: 0.06-0.45).The association between Hcy and CVD was significantly stronger in patients with hypertension with a larger MPV. MPV may modify the contribution of Hcy to CVD events through synergistic interactions with Hcy. These findings suggest that MPV could be monitored and controlled in the prevention of CVD.

Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA-mediated and shRNA-mediated NPRL2 down-regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down-regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down-regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down-regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease-free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down-regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC.

BACKGROUND: Increased blood pressure (BP) variability is positively associated with the risks of cerebral small-vessel disease, cardiovascular events and death. However, no large clinical trials have been published to demonstrate the effect of BP fluctuations during hospitalization on clinical outcomes after ischemic stroke. METHODS: A total of 3972 patients with acute ischemic stroke from 26 participating hospitals were included in this study, and BP fluctuations were calculated using BP data collected during the hospitalization. The primary outcome was composite outcome of death or major disability (modified Rankin Scale score ≥3) within 3 months and secondary outcomes included death, vascular events, and composite outcomes (death or vascular events). RESULTS: Compared with the lowest quartile of systolic BP fluctuations, the adjusted odds ratio associated with the highest quartile was 1.33 ([95% CI, 1.05–1.68]; P trend =0.011) for primary outcome; the adjusted hazard ratios were 2.89 ([95% CI, 1.58–5.32]; P trend P trend =0.071) for vascular events, and 2.06 ([95% CI, 1.32–3.23]; P trend P for linearity=0.0009). CONCLUSIONS: Larger BP fluctuations during hospitalization were associated with an increased risk of adverse outcomes at 3 months after ischemic stroke onset, independent of mean BP. These findings suggested that BP fluctuation should be a risk factor of adverse outcomes after ischemic stroke, which provided a new insight for BP management strategy.

Haemoglobin A1c (HbA1c) is a marker of glycaemic control in type 2 diabetes mellitus (T2DM). Increased waist circumference (WC) is known to be associated with T2DM. Therefore, we investigated the relationship of WC with HbA1c and explored its optimal cutoff for identifying prediabetes and diabetes risk. This study included 2339 participants between 18 and 84 years of age [mean (SD) age, 43.5 (11.9) years] with valid data on WC, HbA1c and related variables in the Shenzhen–Hong Kong United Network on Cardiovascular Disease study. Participants on anti-diabetic medications were excluded. Multiple linear regression was used to investigate the relationship between HbA1c and WC. Cutoff values of WC indicating an HbA1c level of 5.7% and 6.5% were also assessed using optimal binning. There was a significant linear relationship between WC and HbA1c in the overall population (B = 0.261, P B = 0.206, P B = 0.311, P B = 0.201, P B = 0.186, P B = 0.182, P

Researchers have not determined whether the association between growth differentiation factor-15 (GDF-15) levels and stroke outcomes is modified by the diabetes status. We aimed to evaluate the prognostic value of GDF-15 among patients with ischemic stroke stratified by diabetes.A total of 3001 patients with ischemic stroke were selected from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and included in this study. The primary outcome was a composite outcome of death and vascular events at 3 months after acute ischemic stroke. An elevated GDF-15 level was significantly associated with the primary outcome in patients with diabetes but not in those without diabetes (pA modifying effect of the diabetes status on the association between serum GDF-15 levels and ischemic stroke prognosis was observed. Elevated serum GDF-15 levels were associated with the primary outcome within 3 months after ischemic stroke in patients with diabetes, suggesting that GDF-15 may be an important prognostic factor for ischemic stroke in patients with diabetes.

Although some evidence has validated the connection between heterogeneous nuclear ribonucleoprotein C (HNRNPC) and the progression of tumors, a pan-cancer investigation is still required. Thus, we explored the oncogenic effect of HNRNPC across many tumors using The Cancer Genome Atlas datasets. Moreover, short hairpin RNAs (shRNAs) were found to repress HNRNPC in lung adenocarcinoma (LUAD) cells, and the effect on LUAD cells proliferation and metastasis was examined using a Cell Counting Kit-8, transwell, and invasion test. HNRNPC was found to be overexpressed in most cancers, and a divergent relationship was observed between the abnormal levels of HNRNPC and tumor prognosis. HNRNPC level was observed to correlate with the cancer-associated fibroblast infiltration, such as lung cancer. Furthermore, higher HNRNPC levels were found in LUAD tissues and cells. Subsequently, Kaplan-Meier analysis revealed that the increased HNRNPC level was connected with worse overall survival and disease-free survival in LUAD patients. Moreover, HNRNPC silencing reduced the progression of A549 and H1299 cells, including proliferation, migration, and invasion. This is the first pan-cancer investigation that presents a relatively systematic finding of the oncogenic effect of HNRNPC among many cancer types. Our data indicate that HNRNPC facilitates the biological processes of LUAD cells; nevertheless, further research on the mechanism underlying the role of HNRNPC in LUAD development is warranted.

Interleukin-8 (IL-8 or C-X-C motif chemokine ligand 8, CXCL8) is a cytokine secreted by numerous cell types and is best known for its functional roles in inflammatory response by binding to specific receptors (the interleukin-8 receptors, IL-8Rs). From the transcriptomic data of largemouth bass (Micropterus salmoides), we identified an IL-8R that is highly homologous to the functionally validated teleost IL-8Rs. The M. salmoides IL-8 receptor (MsCXCR2) was further compared with the C-X-C motif chemokine receptor 2 subfamily by phylogenetic analysis. Briefly, the full-length CDS sequence of MsCXCR2 was cloned into the pEGFP-N1 plasmid, and the membrane localization of fusion expressing MsCXCR2-EGFP was revealed in HEK293 cells. To determine the functional interaction between IL-8 and MsCXCR2, secretory expressed Larimichthys crocea IL-8 (LcIL-8) was used to stimulate MsCXCR2 expressing cells. MsCXCR2 was demonstrated to be activated by LcIL-8, leading to receptor internalization, which was further revealed by the detection of extracellular regulated protein kinase (ERK) phosphorylation. Quantitative real-time PCR was used to evaluate the expressional distribution and variation of MsCXCR2 in healthy and Nocardia seriolae infected fish. Based on our findings, MsCXCR2 was constitutively expressed in all examined tissues, despite at different levels. Furthermore, gene expression was found to be significantly upregulated in the liver and head kidney of diseased fish. Collectively, our findings reveal the molecular activity of MsCXCR2 and indicate the functional involvement of this IL-8R in the immune response induced by N. seriolae in M. salmoides.

Background: It remains unclear whether different blood pressure management strategies should be administered for acute stroke patients with or without impaired renal function. We conducted a secondary analysis of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke) to investigate the effect of early antihypertensive treatment among patients with acute ischemic stroke according to the baseline renal function assessed by estimated glomerular filtration rates (eGFR). Methods: The CATIS trial randomly assigned 4071 acute ischemic stroke patients with systolic blood pressure between 140 and 220 mm Hg to receive antihypertensive treatment or to discontinue all antihypertensive medications during hospitalization. A primary outcome (composite outcome of death and major disability) and secondary outcomes were compared between antihypertensive treatment and control groups by baseline renal function levels of eGFR values of 2 . Results: At day 14 or hospital discharge, the primary outcome was not significantly different between the antihypertensive treatment and control groups in each subgroup stratified by renal function status ( P =0.98 for homogeneity), and the odds ratios (95% CIs) were 1.23 (0.76–2.02) in patients with eGFR 2 , 0.94 (0.75–1.19) in patients with eGFR values of 60–89 mL/min per 1.73 m 2 , and 1.04 (0.88–1.24) in patients with eGFR ≥90 mL/min per 1.73 m 2 , respectively. In addition, early antihypertensive treatment was not associated with secondary clinical outcomes by baseline renal function ( P >0.05 for all homogeneity). Conclusions: Early antihypertensive treatment had a neutral effect on clinical outcomes in ischemic stroke patients with different renal function status. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01840072.

Statin therapy can effectively reduce recurrent transient ischemic attack (TIA) risk. However, studies have reported that statin use is associated with incidence of diabetes mellitus (DM). Whether statin therapy remains associated with higher DM risk in patients with TIA remains unknown. This study investigated whether statin treatment influences incident DM risk in patients with TIA. We conducted a retrospective cohort study using the Longitudinal Health Insurance Database 2000. Participants who were newly diagnosed with TIA (ICD-9-CM code 435) from 1 January 1997 to 31 December 2011 were recruited. The Kaplan–Meier method and Cox proportional risk model of time-dependent covariance were used. We enrolled 8342 patients with newly diagnosed TIA from 1 January 1997 to 31 December 2011. Of these, 1255 patients were classified as statin users and 7087 as nonusers. During the 14-year follow-up, the incidence of newly diagnosed DM was 0.545-fold lower in the statins group compared with nonusers (95% confidence interval [CI] = 0.457–0.650). According to cumulative defined daily doses (cDDDs), the adjusted hazard ratios for DM were 0.689, 0.594, and 0.463 when patients were treated with statins at cDDDs = 28–89, 90–180, and >180, respectively. In patients with TIA, statin use is associated with a lower incident DM risk compared with the nonuse of statins.

Sphingolipid metabolism (SM) fuels tumorigenesis and the malignant progression of osteosarcoma (OS), which leads to an unfavorable prognosis. Elucidating the molecular mechanisms underlying SM in osteosarcoma and developing a SM-based prognostic signature could be beneficial in the clinical setting. This study included 88 frozen OS samples to recognize the vital SM-relevant genes in the development of OS utilizing univariate Cox regression. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was conducted on the SM- relevant genes to minimize the risk of overfitting. The prognostic signature was generate utilizing the multivariable Cox regression analysis and was verified in the validation cohort. Moreover, cellular and molecular mechanisms associated with SM have an unfavorable prognosis for OS patients and have been widely studied. Resultantly, an SM-based prognostic risk model was established according to critical prognostic genes (CBS, GLB1, and HACD1), which had an excellent ability to predict the prognosis of OS patients (AUC for the train cohort was 0.887 and AUC for validation cohort was 0.737). The high-risk OS patients identified based on this prognostic signature had significantly poor immune microenvironment, indicated by significantly low immune score (mean=216.290 ± 662.463), reduced infiltrations of 25 immune cells, including NK cells (LogFC= -0.3597), CD8+T cells ((LogFC=-0.2346), Cytolytic activity ((LogFC=-0.1998), etc. The immunosuppressive microenvironment could be due to dysregulated SM of glycolipids. Further, a nomogram was constructed by integrating the SM-based prognostic signature and clinical paraments to facilitate clinical application. The nomogram could accurately predict the prognosis of OS invalids. Collectively, this study clarified the function of SM in the development of OS and helped develop a tool for risk stratification based on SM-related genes with application in clinical settings. The results of our study will aid in identifying high-risk patients and provide individualized treatments.

Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large‐scale sequencing studies to discern functional genetic variants and their interactions with clinical and lifestyle risk factors on ischemic stroke are limited. Methods and Results We sequenced functional regions of 740 previously identified genes associated with atherosclerotic disease among 999 ischemic stroke cases and 1001 controls of Chinese ancestry. Multiple logistic regression models were used to examine the associations between variants and ischemic stroke and test interactions between variants and clinical and lifestyle risk factors. Functional variants achieving suggestive significance were replicated in an independent sample of 4724 ischemic stroke cases and 5029 controls. Driven by variant main effects, each minor allele of the correlated rs174535, rs174545, and rs3834458 variants at MYRF‐FADS1‐FADS2 conferred an average 0.83‐fold (95% CI, 0.78–0.88) decreased odds of stroke. Significant main effects of MTHFR rs1801133 missense variant were also observed, with each copy of the A allele associated with a 1.20‐fold (95% CI, 1.13–1.27) higher odds of ischemic stroke. The functional ALDH2 rs671 variant was identified in interaction analyses with alcohol drinking ( Meta‐P =3.39×10 −17 ). Each minor allele conferred a 0.54‐fold (95% CI, 0.45–0.64) decreased odds of stroke among drinkers and a 0.89‐fold (95% CI, 0.83–0.97) decreased odds among nondrinkers. Conclusions Significant associations at MYRF‐FADS1‐FADS2 indicate that genetically elevated polyunsaturated fatty acids may decrease ischemic stroke risk in East Asians. Significant associations at MTHFR and ALDH2 robustly confirm deleterious effects of genetically elevated homocysteine and alcohol intake, respectively, on ischemic stroke.

PURPOSE In vivo range and dose verification based on proton-induced acoustics (protoacoustics) is potentially a useful tool for proton therapy. Built upon our previous study with two-dimensional reconstruction, the time reversal (TR) method was extended to three-dimensional (3D) and evaluated at two treatment sites (head and liver) through simulation, with the emphasis on a number of aspects such as increased spatial coverage, computational workload, and signal interference among slices. METHODS Two mono-energetic pencil beams were modeled in each site. The k-Wave toolbox was used to investigate the propagation and TR reconstruction of acoustic waves. The performance was quantitatively assessed based on mean square error (MSE) for dose verification and Bragg peak localization error (ΔBP ) for range verification, with regard to five parameters: number of sensors, sampling duration, sampling timestep, spill time, and noise level. RESULTS The respective impacts of five parameters are examined. Under the optimum setting, the achievable ΔBP can be limited within 1 voxel (voxel size: 3 × 3 × 3 mm3 ) and the achievable MSE can be limited below 0.02, for the head case (56 sensors) and the liver case (204 sensors), respectively. CONCLUSIONS The feasibility of range and dose verification utilizing the 3D TR method is demonstrated, as the very first step. In spite of several challenges unique to the 3D case (spatial coverage, computational workload, and signal interference among slices, etc.), promising performance is found and can be further improved through optimizing the deployment of sensors. The proposed approach may find potential use in several applications: beam diagnostics, in vivo dosimetry, and treatment monitoring.

Lung cancer is the most common cause of cancer-related death in the world. Long non-coding RNAs (lncRNAs) are longer than 200 nucleotide transcripts, and are not translated into protein. The lncRNA linc00662 is overexpressed in lung cancer; however, its role in lung cancer is still unknown. In our study, by analyzing the TCGA data, we found that linc00662 was overexpressed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We knocked-down the expression of linc00662 using siRNA, and found that silencing linc00662 significantly inhibited the proliferation and colony formation of the lung cancer cell lines A549 and H460. We also found that knockdown of linc00662 increased the expression of the microRNA miR-145-5p and decreased the expression of the platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2) gene. We further show that linc00662 binds with miR-145-5p, and that miR-145-5p binds to the 3′UTR of PAFAH1B2. miR-145-5p negatively regulates PAFAH1B2 both at the mRNA and the protein level. Loss of miR-145-5p abolished the inhibitory effects of silencing linc00662 on the proliferation and colony formation of A549 and H460 cells. These findings indicate that linc00662 functions as an oncogene by acting as a competing endogenous RNA (ceRNA) and sponges and regulates miR-145-5p in lung cancer, and thus may provide a potential target for treating lung cancer.

Liver cancer is the third-most lethal cancer worldwide. Abnormal expression of microRNAs (miRNAs) modulates gene expression to exert oncogenic or tumor-suppressive effects in liver cancer. However, the biological role of miR-1303 in the progression of liver cancer and its regulatory mechanism has not been elucidated.The expression levels of miR-1303 were measured in liver-cancer tissues of patients and cell lines by RT-qPCR. Huh-7 and HepG2 liver-cancer cells were co-transfected by TLN1 and miR-1303 constructs. Cell viability was measured by the CCk-8 assay and colony-formation assay. Flow cytometry was used to measure cell apoptosis. Cell migration and invasion were determined by wound-healing and transwell-chamber assays. RT-PCR and western-blotting were used to determine miR-1303 inhibitor-associated marker expression, such as Bax, cleaved-caspase-3 and cleaved-caspase-9.miR-1303 expression was strongly up-regulated in liver-cancer tissues and cells. Knockdown of miR-1303 attenuated cell proliferation, migration and invasion, and induced apoptosis in liver-cancer cells. Talin 1 (TLN1) and miR-1303 expression were negatively correlated, possibly by miR-1303 targeting the TLN1 gene. TLN1 expression enhanced the efficacy of an miR-1303 inhibitor to reduce liver-cancer cell proliferation and invasion.miR-1303 plays an important role in liver cancer, which is inhibited by TLN1 expression.

We present an approach to estimate with simple instrumentation the amount of red blood cells in the skin microvasculature, designated as parameter LRBC. Variations of parameter LRBC are shown to reflect local changes in the quantity of skin red blood cells during a venous occlusion challenge.To validate a simple algebraic model of light transport in skin using the Monte Carlo method and to develop a measure of the red blood cell content in skin microvessels using the Monte Carlo predictions; to guide the development of an instrument to measure experimentally variations of the amount of red blood cells in the skin.Monte Carlo simulations were carried out in a multilayer model of the skin to compute remitted light intensities as a function of distance from the illumination locus for different values of the skin blood content. The simulation results were used to compute parameter LRBC and its variations with local skin blood content. An experimental setup was developed to measure parameter LRBC in human volunteers in whom skin blood content of the forearm increased during temporary interruption of the venous outflow.In the simulations, parameter LRBC was ∼16 μm in baseline conditions, and it increased in near proportion with the blood content of the skin layers. Measuring the diffusely reflected light intensity 0.5 to 1.2 mm away from the illumination locus was optimal to detect appreciable changes of the reflected light intensity as skin blood content was altered. Parameter LRBC measured experimentally on the human forearm was 17 ± 2 μm in baseline conditions it increased at a rate of 4 ± 2 μm / min when venous outflow was temporarily interrupted.Parameter LRBC derived experimentally with a two-wavelength diffuse reflectometer can be used to measure local variations of the amount of red blood cells in skin microvessels.

The aim of this study is to investigate the capability using the China-PAR stroke equations for predicting 10-year risk of stroke among the Inner Mongolian population in China.A prospective cohort study was conducted among 2535 rural Inner Mongolian residents from June 2002 to July 2012. Participants were categorized into four subgroups according to their 10-year predicted stroke risks calculated using the China-PAR stroke equations:5%, 5-9.9%, 10-19.9%, and ≥20%.The C-statistic of the China-PAR stroke equations for 10-year stroke was 0.58, and the result from Hosmer-Lemeshow 'goodness-of-fit' test showed that the China-PAR stroke equations fitted the Inner Mongolian women well (The China-PAR stroke equations have potential predictive ability for 10-year stroke risk in the rural Inner Mongolian women, while it might not suit the rural Inner Mongolian men well. The performance of China-PAR stroke equations in other ethnic groups in China will need to be further evaluated.

Long noncoding RNAs (lncRNAs) are a kind of molecule that cannot code proteins, and their expression is dysregulated in diversified cancers. LncRNA PITPNA-AS1 has been shown to act as a tumor promoter in a variety of malignancies, but its function and regulatory mechanisms in lung squamous cell carcinoma (LUSC) are yet unknown.The mRNA and protein expression of genes were examined by RT-qPCR, western blot, and IHC assay. The cell proliferation, migration, invasion, and stemness were detected through CCK-8, colony formation, Transwell and spheroid formation assays. The CD44The lncRNA PITPNA-AS1 had increased expression in LUSC and was linked to a poor prognosis. In LUSC, PITPNA-AS1 also enhanced cell proliferation, migration, invasion, and stemness. This mechanistic investigation showed that PITPNA-AS1 absorbed miR-223-3p and that miR-223-3p targeted PTN. MiR-223-3p inhibition or PTN overexpression might reverse the inhibitory effects of PITPNA-AS1 suppression on LUSC progression, as demonstrated by rescue experiments. In addition, the PITPNA-AS1/miR-223-3p/PTN axis accelerated tumor development in vivo.It is the first time we investigated the potential role and ceRNA regulatory mechanism of PITPNA-AS1 in LUSC. The data disclosed that PITPNA-AS1 upregulated PTN through sponging miR-223-3p to enhance the onset and progression of LUSC. These findings suggested the ceRNA axis may serve as a promising therapeutic biomarker for LUSC patients.

Rupture and hemorrhage is the most serious complication of cerebral arteriovenous malformation(cAVMs), and have a significant impact on quality of life.We investigated the hematoxylin and eosin staining and ultrastructural features of cAVMs and characterized the abnormal vascular structure of cAVMs.Light and electron microscopy were performed on a series of pathological specimens obtained from 12 patients with cAVMs who underwent surgical resection for the first time without radiosurgery or embolization therapy.In tunica intima, we found that the vascular endothelial cells of cAVMs were damaged, and the lysis of the cell body occurred in multiple regions. In tunica media, the arrangement of the elastic layer was disordered, and the thickness was uneven. Part of the structure of the elastic lamina was missing. The part of tunica adventitia was fractured and discontinuous. In addition, we also observed the phenomenon that different blood vessels share the same vascular wall. Macrophage phagocytosis and lymphocyte infiltration in the adventitial region of ruptured cAVMs. Abnormal lipid deposition in vascular endothelial cells and smooth muscle cells.The structural incompleteness of cAVMs may be an important cause of hemorrhage.

Purpose Accurate dose calculation is a critical step in proton therapy. A novel machine learning-based approach was proposed to achieve comparable accuracy to that of Monte Carlo simulation while reducing the computational time. Methods Computed tomography-based patient phantoms were used and three treatment sites were selected (thorax, head, and abdomen), comprising different beam pathways and beam energies. The training data were generated using Monte Carlo simulations. A discovery cross-domain generative adversarial network (DiscoGAN) was developed to perform the mapping between two domains: stopping power and dose, with HU values from CT images incorporated as auxiliary features. The accuracy of dose calculation was quantitatively evaluated in terms of mean relative error (MRE) and mean absolute error (MAE). The relationship between the DiscoGAN performance and other factors such as absolute dose, beam energy and location within the beam cross-section (center and off-center lines) was examined. Results The DiscoGAN model is found to be effective in dose calculation. For the abdominal case, the MRE is found to 1.47% (mean), 3.30% (maximum) and 0.67% (minimum). For the thoracic case, the MRE is found to ~2.43% (mean), 4.80% (maximum) and 0.71% (minimum). For the head case, the MRE is found to ~2.83% (mean), 4.84% (maximum) and 1.01% (minimum). Comparable accuracy is found in the independent validation dataset (different CT images), achieving a mean MRE of ~1.65% (thorax), 4.02% (head) and 1.64% (abdomen). For the energy span between 80 and 130 MeV, no strong dependency of accuracy on beam energy is found. The results imply that no systematic deviation, either over-dose or under-dose, occurs between the predicted dose and raw dose. Conclusion The DiscoGAN framework demonstrates great potential as a tool for dose calculation in proton therapy, achieving comparable accuracy yet being more efficient relative to Monte Carlo simulation. Its comparison with the pencil beam algorithm (PBA) will be the next step of our research. If successful, our proposed approach is expected to find its use in more advanced applications such as inverse planning and adaptive proton therapy.

Background and aims Angiopoietin-like protein 4 (ANGPTL-4) had been reported to be associated with the risk of ischemic stroke, but its prognostic value remained unclear. The aim of this study was to investigate the association between plasma ANGPTL-4 concentrations and prognosis of ischemic stroke. Methods Baseline plasma ANGPTL-4 concentrations were measured in 3379 acute ischemic stroke patients. The primary outcome was a combination of death or major disability (modified Rankin Scale score, ≥3) at 3 months after ischemic stroke, and secondary outcomes included major disability, death, stroke recurrence and vascular events. Results At 3 months after ischemic stroke, 850 (26.16%) participants experienced major disability or died (750 major disabilities and 100 deaths). After adjusting for important covariates, odds ratios for the highest tertile of plasma ANGPTL-4 concentrations were 1.59(1.22-2.06) for primary outcome, 1.53(1.18-1.97) for major disability and 2.03(1.03-4.00) for death when compared to the lowest tertile of plasma ANGPTL-4 concentrations. For 1-SD increase of log-ANGPTL-4 concentrations (0.44 ng/ml), the adjusted odds ratios were 1.24(1.11-1.38), 1.14(1.03-1.27) and 1.72(1.32-2.23), respectively. Adding ANGPTL-4 to a model containing conventional risk factors improved risk prediction for composite outcome of death and major disability (net reclassification improvement index=11.36%, p =0.014; integrated discrimination improvement=0.22%, p =0.033). There were no significant associations between plasma ANGPTL-4 concentrations and risks of stroke recurrence and vascular events. Conclusion Higher plasma ANGPTL-4 concentration was associated with poor prognosis in acute ischemic stroke patients, suggesting that ANGPTL-4 might be a prognostic marker for ischemic stroke.

Background and Purpose: Complement C3 has been implicated in inflammation and ischemia/reperfusion injury, but its impact on the prognosis of ischemic stroke remains unclear. Aim of this study was to prospectively investigate the association between serum complement C3 and adverse clinical outcomes after ischemic stroke. Methods: We measured serum complement C3 levels for 3474 patients with ischemic stroke in 26 participating hospitals and collected data of clinical outcomes at 3 months after ischemic stroke. The primary outcome was composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset and secondary outcomes included major disability, death, and vascular events. Results: During 3 months of follow-up, 866 participants (25.4%) developed primary outcome. After multivariate adjustment, elevated serum complement C3 levels were associated with increased risk of primary outcome (odds ratio, 1.30 [95% CI, 1.02–1.65]; P trend =0.038) when 2 extreme tertiles were compared. Each SD increase of log-transformed complement C3 was associated with 13% (95% CI, 2%–25%) increased risk of primary outcome. Multivariable-adjusted spline regression model showed a linear relationship between serum complement C3 and the risk of primary outcome ( P linearity =0.022). Addition of serum complement C3 to conventional risk factors significantly improved the risk prediction of primary outcome (net reclassification index: 8.87%, P =0.028; integrated discrimination index: 0.19%, P =0.029). Conclusions: High serum complement C3 levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that serum complement C3 may be a valuable prognostic biomarker for ischemic stroke.

RNA sequencing (RNA-seq) is a well-validated tool for detecting gene fusions in fresh-frozen tumors; however, RNA-seq is much more challenging to use with formalin-fixed, paraffin-embedded (FFPE) tumor samples. We evaluated the performance of RNA-seq to detect gene fusions in clinical FFPE tumor samples. Our assay identified all 15 spiked-in NTRK fusions from RNA reference material and six known fusions from five cancer cell lines. Limit of detection for the assay was assessed with a series of dilutions of RNA from the cell line H2228. These fusions can be detected when the dilution is down to 10%. Good intra-assay and interassay reproducibility was observed in three specimens. For clinical validation, the assay detected 10 of 12 fusions initially identified by a DNA panel (covering 23 gene fusions) in clinical specimens (83.3% sensitivity), whereas one fusion (MET fusion) was identified in another 34 fusion-negative tumor specimens as determined by the DNA panel (negative prediction value of 94.3%). This MET fusion was confirmed by RT-PCR and Sanger sequencing, which found that this is a false-negative result for the DNA panel. The assay also identified 26 extra fusions not covered by the DNA panel, 20 (76.9%) of which were validated by RT-PCR and Sanger sequencing. Therefore, this RNA assay has reasonable performance and could complement DNA-based next-generation sequencing assays.

Targeting the SARS-CoV-2 main protease Vaccines are an important tool in the fight against COVID-19, but developing antiviral drugs is also a high priority, especially with the rise of variants that may partially evade vaccines. The viral protein main protease is required for cleaving precursor polyproteins into functional viral proteins. This essential function makes it a key drug target. Qiao et al. designed 32 inhibitors based on either boceprevir or telaprevir, both of which are protease inhibitors approved to treat hepatitis C virus. Six compounds protected cells from viral infection with high potency, and two of these were selected for in vivo studies based on pharmokinetic experiments. Both showed strong antiviral activity in a mouse model. Science, this issue p. 1374, Designed SARS-CoV-2 Mpro (main protease) inhibitors display excellent antiviral activity both in vitro and in a transgenic mouse model., The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

Background and aims Whether the prognostic value of matrix metalloproteinase-9 (MMP-9) is modified by patients' dyslipidemia status is unknown. The aim of present study was to evaluate the prognostic effect of MMP-9 among ischemic stroke patients stratified by dyslipidemia status. Methods and results MMP-9 levels were measured for 2977 acute ischemic stroke patients from 26 participating hospitals across China, and data of clinical outcomes within one year after ischemic stroke was collected. The primary outcome was a composite outcome of major disability and death at one year after stroke onset, and secondary outcomes were major disability, death, vascular events and recurrent stroke. The association between MMP-9 and primary outcome was appreciably modified by dyslipidemia status (Pinteraction = 0.048). After multivariate adjustment, increased MMP-9 level was associated with increased risk of primary outcome at one year after ischemic stroke in the patients with dyslipidemia (odds ratio, 1.34; 95% confidence interval, 1.06–1.79), but not in those without dyslipidemia (odds ratio, 1.23; 95% confidence interval, 0.90–1.68). Increased MMP-9 was also significantly associated with major disability, death and vascular events in the patients with dyslipidemia but not in those without dyslipidemia (P for interaction Conclusion Increased MMP-9 was associated with poor prognosis within one-year after stroke only in patients with dyslipidemia, suggesting that the prognostic value of MMP-9 be modified by dyslipidemia status of ischemic stroke patients. Further prospective study from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

Early screening of PDAC (pancreatic ductal adenocarcinoma) based on plain CT (computed tomography) images is of great significance. Therefore, this work conducted a radiomics-aided diagnosis analysis of PDAC based on plain CT images. We explored a novel MSTA (multiresolution-statistical texture analysis) architecture to extract texture features and built machine learning models to classify PDACs and HPs (healthy pancreases). We also performed significance tests of differences to analyze the relationships between histopathological characteristics and texture features. The MSTA architecture originates from the analysis of histopathological characteristics and combines multiresolution analysis and statistical analysis to extract texture features. The MSTA architecture achieved better experimental results than the traditional architecture that scales the coefficient matrices of the multiresolution analysis. In the validation of the classifications, the MSTA architecture achieved an accuracy of 81.19% and an AUC (area under the ROC (receiver operating characteristic) curve) of 0.88 (95% confidence interval: 0.84-0.92). In the test of the classifications, it achieved an accuracy of 77.66% and an AUC of 0.79 (95% confidence interval: 0.71-0.87). Moreover, the significance tests of differences showed that the extracted texture features may be relevant to the histopathological characteristics. The MSTA architecture is beneficial for the radiomics-aided diagnosis of PDAC based on plain CT images. Its texture features can potentially enhance radiologists' imaging interpretation abilities.

Phospholipase C epsilon 1 (PLCE1) and the competing endogenous RNA (ceRNA) network are crucial for tumorigenesis and the progression of esophageal squamous cell carcinoma (ESCC). However, whether PLCE1 can regulate the ceRNA network in ESCC has not been clarified. In the present study, we aimed to identify the PLCE1‑regulated ceRNA network and further elucidate the regulatory mechanisms by which ESCC is promoted. Microarray analysis was used to identify differentially expressed lncRNAs (DELs) and differentially expressed genes (DEGs) from three pairs of samples of PLCE‑silenced Eca109 and control Eca109 cells. Next, the ceRNA regulatory network was established and visualized in Cytoscape, and functional enrichment analysis was performed to analyze DEGs from ceRNAs. Protein‑protein interaction (PPI) networks among the DEGs were established by the STRING database to screen hub genes. Kaplan‑Meier survival analysis was used to validate hub genes. Finally, PLCE1‑related hub gene/lncRNA/miRNA axes were also constructed based on the ceRNA network. A total of 105 DELs and 346 DEGs were found to be dysregulated in the microarray data (|log2FC| >1.5, adjusted P

Given the increasing incidence of neurodegenerative disease (ND), recent research efforts have intensified the search for curative treatments. Despite significant research, however, existing therapeutic options for ND can only slow down the progression of the disease, but not provide a cure. Light therapy (LT) has been used to treat some mental and sleep disorders. This review illustrates recent studies of the use of LT in patients with ND and highlights its potential for clinical applications. The literature was collected from PubMed through June 2020. Selected studies were primarily English articles or articles that could be obtained with English abstracts and Chinese main text. Articles were not limited by type. Additional potential publications were also identified from the bibliographies of identified articles and the authors’ reference libraries. The identified literature suggests that LT is a safe and convenient physical method of treatment. It may alleviate sleep disorders, depression, cognitive function, and other clinical symptoms. However, some studies have reported limited or no effects. Therefore, LT represents an attractive therapeutic approach for further investigation in ND. LT is an effective physical form of therapy and a new direction for research into treatments for ND. However, it requires further animal experiments to elucidate mechanisms of action and large, double-blind, randomized, and controlled trials to explore true efficacy in patients with ND.

Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.

Rationale N-terminal pro-brain natriuretic peptide (NT-proBNP) and galectin-3 are important biomarkers related to ischemic stroke. However, the predictive value of the combination of them has not been examined in previous studies. Objective The aim of this study was to investigate the combined effect of NT-proBNP and galectin-3 on clinical outcomes in ischemic stroke patients. Methods A total of 2694 patients (63.62% males; mean age = 62.4 in admission) with serum NT-proBNP and galectin-3 measured simultaneously were included in this study. The primary outcome was composite outcome of death or major disability 1 year after stroke onset. Secondary outcomes were separately death, major disability, vascular events and the composite outcome of vascular events or death. The participants were divided into 4 groups according to NT-proBNP and galectin-3. Odd ratios (ORs; for nonevent outcome without time variables: primary outcome, major disability) or hazard ratios (HRs; for event outcome with time variables: death, vascular events, and the composite outcome of vascular events or death) were calculated to assess the association of NT-proBNP and galectin-3 status with adverse outcomes. Results At the 1-year follow-up, 589 patients experienced a primary outcome after stroke onset. After adjustment for potential confounders, high NT-proBNP/high galectin-3 group were associated with increased risks of primary outcome (OR: 1.43; 95% confidence interval [CI], 1.02–2.00; P value = 0.039), death (HR: 2.74; 95% CI, 1.42–5.29; P value = 0.003), and the composite outcome of vascular events or death (HR: 1.66; 95% CI, 1.06–2.58; P value = 0.026). Statistical tests for interactions between the 4 groups and primary outcome or death were not significant (all P interaction > 0.05). Conclusion Simultaneously increased NT-proBNP and galectin-3 significantly increased the risk of poor clinical outcomes 1 year after ischemic stroke. Using NT-proBNP and galectin-3 together can result in an accurate prediction of ischemic stroke prognosis.

Apoptosis of osteoblasts caused by glucocorticoid (GC) is the biological basis of steroid‐induced avascular necrosis of the femoral head (SANFH). We found that GC can induce osteoblast apoptosis and autophagy through the ROS/JNK/c‐Jun signaling pathway, which contributes to SANFH. Therefore, the autophagy inhibitor 3‐MA might have potential for development into a treatment for SANFH., Osteonecrosis of the femoral head (ONFH) is a common clinical disease with a high disability rate. Apoptosis of osteoblasts caused by high‐dose short‐term or low‐dose long‐term glucocorticoid (GC) administration is the biological basis of steroid‐induced avascular necrosis of the femoral head (SANFH). The pathogenesis of SANFH has not yet been fully elucidated, and there is currently a lack of effective clinical treatments. Here, we investigated the role of the reactive oxygen species (ROS)/JNK/c‐Jun signaling pathway in SANFH. Dexamethasone (Dex) was used to induce apoptosis in osteoblasts, and this resulted in a significant increase in levels of p‐JNK, p‐c‐Jun, Bax, caspase‐3, caspase‐9, cytochrome C, Beclin‐1, and LC3, and a decrease in levels of P62 and Bcl‐2. In addition, intracellular ROS levels were increased and mitochondrial membrane potential was decreased. Administration of 3‐MA, an autophagy inhibitor, attenuated Dex‐mediated changes in autophagy and apoptosis. A rat model of ONFH exhibited severe bone trabecular hollow bone pits along with a significant increase in femoral head cell apoptosis compared with the control group. Additionally, micro‐CT analysis showed that both bone tissue content and femoral head integrity were significantly reduced in the ONFH group. Furthermore, 3‐MA treatment decreased the effect of Dex on GC‐induced ONFH and osteoblast apoptosis in rats and could counteract microstructure destruction due to femoral head necrosis. In summary, our data suggest that GC can induce osteoblast apoptosis and autophagy through the ROS/JNK/c‐Jun signaling pathway, which contributes to ONFH.

Osteoarthritis (OA) is an ageing‐related disease characterized by articular cartilage degradation and joint inflammation. circRNA has been known to involve in the regulation of multiple inflammatory diseases including OA. However, the mechanism underlying how circRNA regulates OA remains to be elucidated. Here, we report circANKRD36 prevents OA chondrocyte apoptosis and inflammation by targeting miR‐599, which specifically degrades Casz1. We performed circRNA sequencing in normal and OA tissues and found the expression of circANKRD36 is decreased in OA tissues. circANKRD36 is also reduced in IL‐1β–treated human chondrocytes. FACS analysis and Western blot showed that the knockdown of circANKRD36 promotes the apoptosis and inflammation of chondrocytes in IL‐1β stress. We then found miR‐599 to be the target of circANKRD36 and correlate well with circANKRD36 both in vitro and in vivo. By database analysis and luciferase assay, Casz1 was found to be the direct target of miR‐599. Casz1 helps to prevent apoptosis and inflammation of chondrocytes in response to IL‐1β. In conclusion, our results proved circANKRD36 sponge miR‐599 to up‐regulate the expression of Casz1 and thus prevent apoptosis and inflammation in OA.

IntroductionThis study aimed to identify whether interleukin-6 (IL-6) is better than C-reactive protein (CRP) for the prediction of severe acute pancreatitis (SAP), infected pancreatic necrosis (IPN), and mortality.MethodsSixty-seven patients with acute pancreatitis (AP) who were hospitalized within 48 h of onset and received serum CRP and IL-6 tests from September 2018 to September 2019 were included. Spearman’s correlation was performed to assess their associations with severity. The areas under the curve (AUCs) for the prediction of SAP, organ failure, pancreatic necrosis, IPN, and mortality were estimated using receiver operating characteristic curves.ResultSerum CRP and IL-6 levels were significantly positively correlated with the severity of AP (p < 0.05). The AUC for the prediction of SAP based on the CRP level was 0.78 (95% CI, 0.66–0.89) and that based on the IL-6 level was 0.69 (95% CI, 0.56–0.82). For the prediction of organ failure and pancreatic necrosis, CRP was more accurate than IL-6 (AUC 0.80 vs. 0.72 and 0.75 vs. 0.68, respectively). However, CRP was less accurate than IL-6 for predicting mortality and IPN (AUC 0.70 vs. 0.75 and 0.65 vs. 0.81, respectively). Systemic inflammatory response syndrome plus CRP was more accurate than systemic inflammatory response syndrome plus IL-6 (AUC 0.79 vs. 0.72) for the prediction of SAP.ConclusionsIL-6 was more accurate than CRP for predicting mortality and IPN in patients with AP.

Objectives To investigate the correlation between the histopathology of the kidney and clinical indicators in patients with lupus nephritis (LN) using magnetic resonance imaging (MRI). Methods A total 50 female participants were enrolled in the study. Thirty patients with LN were divided into types 2, 3, 4, and 5, according to their pathological features. The control group consisted of 20 healthy female volunteers. Serum creatinine, C3, C1q, and anti-ds-DNA were measured. Conventional MRI, DTI, DWI, and BOLD scanning was performed to obtain the FA, ADC, and R2* values for the kidney. Results Compared with the control group, FA and the ADC were decreased in patients with LN, while the R2* value was increased (P P P P P Conclusions MRI examination in female patients with LN was correlated with pathologic test results, which may have clinical significance in determining the disease’s severity, treatment, and outcome.

The dynamics of complex diseases are not always smooth; they are occasionally abrupt, i.e. there is a critical state transition or tipping point at which the disease undergoes a sudden qualitative shift. There are generally a few significant differences in the critical state in terms of gene expressions or other static measurements, which may lead to the failure of traditional differential expression-based biomarkers to identify such a tipping point. In this study, we propose a computational method, the direct interaction network-based divergence, to detect the critical state of complex diseases by exploiting the dynamic changes in multivariable distributions inferred from observable samples and local biomolecular direct interaction networks. Such a method is model-free and applicable to both bulk and single-cell expression data. Our approach was validated by successfully identifying the tipping point just before the occurrence of a critical transition for both a simulated data set and seven real data sets, including those from The Cancer Genome Atlas and two single-cell RNA-sequencing data sets of cell differentiation. Functional and pathway enrichment analyses also validated the computational results from the perspectives of both molecules and networks.

Recently, ferroptosis as new regulatory necrosis has attracted the scientific community. However, the study focused on the effect of ferroptosis on osteocytes in steroid (glucocorticoid)-induced osteonecrosis of the femoral head (SONFH) is still scarce. In this study, we use bioinformatic analysis to screen out differentially expressed genes (DEGs) in osteoblasts that treated by dexamethasone (Dex) in GSE10311 and found these DEGs are enriched in the ferroptosis signaling pathway. The results in vitro experiments show that Dex can induce MC3T3-E1 cells ferroptosis by down-regulating SLC7A11. Specifically, Dex inhibits the expression of SLC7A11/GPX4, decreases the activity of the intracellular antioxidant system such as intracellular glutathione (GSH), while increasing Malondialdehyde (MDA), reactive oxygen species (ROS), and lipid ROS, and reduces the volume of mitochondria, the mitochondrial ridges and a series of obvious ferroptosis features. The overexpression of SLC7A11 and the use of ferroptosis inhibitor (Fer-1) can reverse the Dex-induced MC3T3 ferroptosis. Dex can induce an increase in the expression of p53 and knocking down the expression of p53 by small interfering ribonucleic acid (siRNA) can reverse the suppression of SLC7A11 and GPX4 expression in MC3T3-E1 and MOLY4 cells, thereby reducing the production of ferroptosis. Thus, this study demonstrated that Dex induces MC3T3-E1cells ferroptosis via p53/SLC7A11/GPX4 pathway. The present finding offers novel insight to understand the underlying molecular mechanisms for glucocorticoid-induced osteonecrosis. Moreover, the suppression of ferroptosis may be a novel and promising treatment option for SONFH.

Mitochondria, as the "the power plants" of cells, have been extensively studied because of their biological functions of providing energy and participating in signaling pathways. In parallel, calcium (Ca

Arteriovenous malformations (AVMs) are the most common types of cerebral vascular malformations, which are dynamic lesions with de novo growth potentials. The dysfunction of endothelial cells has been postulated to play a role in the pathogenesis of brain AVMs. mTOR-FABP4 signal enhances the angiogenic responses of endothelial cells and is not activated in the normal cerebral vasculature. Herein, we investigated the hypothesis that the mTOR-FABP4 signal may be activated in brain AVMs. The abundance of molecules in mTOR-FABP4 signal expression was detected by immunohistochemistry and Western blotting; special expressing cells were further characterized by double immunofluorescence using antibodies against various cell-specific markers. Next, several functional assays were performed to analyze the influence of the mTOR-FABP4 signal on proliferation, apoptosis, migration, and vascular tube formation of endothelial cells in human umbilical vein endothelial cells (HUVECs) using rapamycin and L-leucine. The expression of mTOR, p-mTOR, and FABP4 was increased in endothelial cells of human brain AVMs. Endothelial cell mTOR and p-mTOR expression were present in 70% and 55% of brain AVMs, respectively. Moreover, a population of FABP4-positive endothelial cells was detected in 80% of brain AVMs. The mTOR-FABP4 signal was activated and inhibited by L-leucine and rapamycin in HUVECs. The proliferation, apoptosis, migration, and vascular tube formation of endothelial cells could be inhibited by rapamycin. The mTOR-FABP4 signal was activated in human brain AVMs, and the mTOR-FABP4 signal was involved in proliferation, apoptosis, migration, and the vascular tube formation of endothelial cells. Taken together, whether rapamycin has therapeutic potential for treating human brain AVMs is worthy of further study. KEY MESSAGES : We confirmed that the mTOR- FABP4 pathway is activated in human brain arteriovenous malformations. We confirmed that mTOR signaling pathway affects endothelial cell function by regulating proliferation, migration, apoptosis, and tube formation of endothelial cell. Our study can provide theoretical support for mTOR pathway inhibitors in the treatment of human brain arteriovenous malformations.

High mindfulness individuals have been found to perform better on motor tasks under various conditions, but it is unknown whether mindfulness and performance relate when performing under pressure or using different types of self-talk with different motor tasks. In this study, 46 male participants ( Mage = 21.4, SD = 1.72 years) with high mindfulness ( n = 23) and low mindfulness ( n = 23) performed dart-throwing and two-hand coordination tasks under pressure and non-pressure conditions and when using instructional and unrelated self-talk. First, on the two-hand coordination task, a three-way mixed ANOVA found: (a) a significant 3-way interaction in which a significantly poorer performance occurred under pressure (vs. without pressure), with low (vs. high) mindfulness and when using unrelated (vs. instructional) self-talk and (b) a significant interaction in which, both under pressure and not, both high and low mindfulness participants performed comparably when using instructional (vs. unrelated) self-talk. Second, on the dart-throwing task, mindfulness interacted with self-talk such that both high and low mindfulness participants performed better when using instructional self-talk, and pressure interacted with self-talk such that participants using instructional (vs. unrelated) self-talk performed better in both pressure and non-pressure conditions. We concluded that instructional self-talk was a useful cognitive strategy, perhaps particularly in pressure conditions and regardless of the degree of mindfulness, and its effectiveness extended to two different motor tasks. We discussed the theoretical implications of these findings, in terms of attention theory, self-talk, and motor control; and we highlighted our study’s limitations and practical applications and gave recommendations for future research.

Background and Aims Accumulating studies identified that BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is integrally involved in the initiation and development of tumors. Nevertheless, the precise biological role and underlying mechanisms of BUB1B in hepatocellular carcinoma (HCC) remain indistinct. Method To figure out the role of BUB1B in HCC, we first assessed its expression using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We then verified BUB1B expression in HCC tissues, nontumor tissues, and HCC cell lines through western blotting, quantitative reverse transcription‐polymerase chain reaction, and immunohistochemistry. To explore the specific function of BUB1B in HCC in vivo and in vitro, we performed the flow cytometry, Cell Counting Kit‐8, 5‐ethynyl‐2′‐deoxyuridine incorporation, colony formation, Transwell, wound‐healing, subcutaneous tumor growth, and metastasis assays. Additionally, we identified the BUB1B‐regulated pathways involved in HCC by using gene set enrichment analysis. Results Our data displayed that higher BUB1B expression was detected in HCC tissues and HCC cell lines. The overexpression of BUB1B was positively correlated with adverse clinicopathological characteristics. Survival analyses showed that lower recurrence‐free and overall survival rates were correlated with the overexpression of BUB1B in patients with HCC. Moreover, the malignancy of HCC was facilitated by BUB1B both in vivo and in vitro. Lastly, the results were confirmed by western blots, which showed that BUB1B upregulated mTORC1 signaling pathway in HCC. Meanwhile, the oncogenic effect of BUB1B will be impaired when the mTORC1 signaling pathway was inhibited by rapamycin. Conclusion We highlighted that BUB1B played an oncogenic role in HCC and was identified as a possible clinical prognostic factor and a potential novel therapeutic target for HCC., Our study confirmed that BUB1B is overexpressed in HCC tissues and cell lines, and the overexpression of BUB1B is highly correlated to adverse clinicopathological features, lower recurrence‐free survival and overall survival rate in patients with HCC. Our results revealed the oncogenic role of BUB1B in HCC through a series of functional assays. Moreover, we identified the BUB1B/mTORC1 signaling axis as a critical regulator of the progression in HCC.

Tissue engineering using adult human mesenchymal stem cells (MSCs) seeded within biomaterial scaffolds has shown the potential to enhance bone healing. Recently, we have developed an injectable, biodegradable methacrylated gelatin‐based hydrogel, which was especially effective in producing scaffolds in situ and allowed the delivery of high viable stem cells and gene vehicles. The well‐demonstrated benefits of recombinant adeno‐associated viral (rAAV) vector, including long‐term gene transfer efficiency and relative safety, combination of gene and cell therapies has been developed in both basic and translational research to support future bone tissue regeneration clinical trials. In this study, we have critically assessed the applicability of single‐step visible light (VL) photocrosslinking fabrication of gelatin scaffold to deliver rAAV encoding human bone morphogenetic protein‐2 (BMP‐2) gene to address the need for sustained BMP‐2 presence localized within scaffolds for the repair of cranial bone defect in mouse model. In this method, rAAV‐BMP‐2 and human bone marrow‐derived MSCs (hBMSCs) were simultaneously included into gelatin scaffolds during scaffold formation by VL illumination. We demonstrated that the subsequent release of rAAV‐BMP‐2 constructs from the scaffold matrix, which resulted in efficient in situ expression of BMP‐2 gene by hBMSCs seeded within the scaffolds, and thus induced their osteogenic differentiation without the supplement of exogenous BMP‐2. The reparative capacity of this novel stem cell‐seeded and gene‐activated scaffolds was further confirmed in the cranial defect in the severe combined immunodeficiency mice, revealed by imaging, histology, and immunohistochemistry at 6 weeks after cranial defect treatment., Schematic diagram of adeno‐associated viral (AAV)‐activated visible light photocrosslinking scaffold for cranial bone defect repair in mice. AAV6‐human bone morphogenetic protein‐2 (BMP‐2) vector and human bone marrow‐derived mesenchymal stem cells (hBMSCs) were simultaneously incorporated into methacrylated gelatin scaffolds during visible light mediated photocrosslinking. We hypothesize that the released AAV6‐BMP‐2 construct from the matrix would result in efficient expression of BMP‐2 gene from hBMSCs co‐seeded within the scaffolds, promoting their osteogenic differentiation, and generating new bone.

We demonstrated that postoperative mesenchymal circulating tumor cell (mCTC) in peripheral blood were independent risk factors for the recurrence of hepatocellular carcinoma (HCC) after radical resection. However, few studies have been conducted on the efficacy and survival benefit of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) for patients with mCTC-positive HCC. We evaluated the effect of PA-TACE on the prognosis of mCTC-positive/mCTC-negative HCC patients. A total of 261 HCC patients from February 2014 to December 2017 undergoing curative hepatectomy were included in this study. Recurrence-free survival (RFS) rates, overall survival (OS) rates, and prognostic factors were analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. The results showed that 57.8% (59/102) mCTC-positive and 43.4% (69/159) mCTC-negative patients underwent PA-TACE. Multivariate analyses demonstrated that PVTT (HR 2.370; 95% CI, 1.535–3.660; P

Background Snoring source analysis is essential for an appropriate surgical decision for both simple snorers and obstructive sleep apnea/hypopnea syndrome (OSAHS) patients. Objective As snoring sounds carry significant information about tissue vibrations within the upper airway, a new feature entitled compressed histogram of oriented gradients (CHOG) is proposed to recognize vibration patterns of the snoring source acoustically by compressing histogram of oriented gradients (HOG) descriptors via the multilinear principal component analysis (MPCA) algorithm. Methods Each vibration pattern corresponds to a sole or combinatorial vibration among the four upper airway soft tissues of soft palate, lateral pharyngeal wall, tongue base, and epiglottis. 1037 snoring events from noncontact sound recordings of 76 simple snorers or OSAHS patients during drug-induced sleep endoscopy (DISE) were evaluated. Results With a support vector machine (SVM) as the classifier, the proposed CHOG achieved a recognition accuracy of 89.8% for the seven observable vibration patterns of the snoring source categorized in our most recent work. Conclusion The CHOG outperforms other single features widely used for acoustic analysis of sole vibration site.

The natriuretic peptides (NPs) system, and mainly atrial natriuretic peptide (ANP), plays a key role in human metabolism and cardiometabolic disorders. Due to differences in NP levels and in prevalence of metabolic syndrome (MetS) between men and women, we aimed to explore the gender difference of association between N-terminal pro-atrial natriuretic peptide (NT-proANP) and MetS in a general population in China. Participants’ weight, height, waist circumference, blood pressure, plasma NT-proANP, and other traditional biomarkers were measured. Multivariate logistic regression models were used to determine the association between plasma NT-proANP and MetS, and the odds ratio (OR) and 95% confidence interval (CI) were calculated for men and women, respectively. Among 2203 participants, 1361 (61.78%) were women, 687(30.77%) participants had MetS, and the average age was 53 years. Women had a higher level of NT-proANP than men. However, adjusted logistic regression demonstrated that men in the upper quartile group of NT-proANP had 0.60 (95% CI 0.39–0.92) times the risk of having MetS, while women in the upper quartile group had 1.10 (95% CI 0.77–1.56) times the risk of having MetS compared to the lower quartile group. Furthermore, with the increase of the level of NT-proANP, the ORs showed a declining trend in men (P = 0.017), but it was not statistically significant among women (P = 0.700). There are gender differences in the relationship between NT-proANP and MetS, while an inverse association between plasma NT-proANP and MetS in men suggests that higher levels of NT-proANP may be a protective factor for MetS.

Background S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts. Methods Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events. Results Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66–2.68) for the primary outcome and 1.62 (95% CI, 1.27–2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10–8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38–3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%–39%; P Conclusions High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.

As an indispensable structure protein, the herpes simplex virus 1 (HSV-1) UL6 has been described to exert numerous roles in viral proliferation. However, its exact subcellular localization and subcellular transport mechanism is not well known. In the present study, by utilizing confocal fluorescent microscopy, UL6 was shown to mainly locate in the nucleus in enhanced yellow fluorescent protein or Flag tag fused expression plasmid-transfected cells or HSV-1-infected cells, whereas its predicted nuclear localization signal was nonfunctional. In addition, by exploiting dominant negative mutant and inhibitor of different nuclear import receptors, as well as co-immunoprecipitation and RNA interference assays, UL6 was established to interact with importin α1, importin α7 and transportin-1 to mediate its nuclear translocation under the help of Ran-mediated GTP hydrolysis. Accordingly, these results will advance the knowledge of UL6-mediated biological significances in HSV-1 infection cycle.

Our purpose was to compare long-term survival outcomes and sequelae between child and adult nasopharyngeal carcinoma (NPC) in the era of intensity modulated radiation therapy.Data on 285 patients with NPC aged ≤18 years at diagnosis and treated with intensity modulated radiation therapy between January 2004 and November 2016 were retrospectively reviewed. A propensity score matching method was adopted to screen matched adult patients with NPC at a ratio of 1:3. Survival outcomes and treatment-related toxicities between child and adult groups were compared.In total, 159 children and 477 adult patients with NPC were included in this study. The 5-year overall survival, distant metastasis-free survival, locoregional relapse-free survival, and disease-free survival between children and adults were 89.2% versus 83.6% (P = .144), 88.7% versus 83.5% (P = .124), 96.4% versus 89.1% (P = .013), and 86.5% versus 77.3% (P = .021), respectively. Subgroup analyses revealed that the young age was an independent prognostic factor of overall survival, distant metastasis-free survival, and locoregional relapse-free survival in the advanced N stage (N2-3) group and disease-free survival in the advanced T stage (T3-4) group and N2-3 and stage III-IVA groups. The most common sequela was ototoxicity (68.9%) in child patients and xerostomia (70.8%) in adult patients. Adult survivors had a significantly higher incidence of grade 3 to 4 late toxicities in xerostomia (17.6% vs 8.9%; P = .004), skin dystrophy (9.3% vs 3.7%; P = .022), neck fibrosis (8.3% vs 4.4%; P.001), and radiation encephalopathy (0.8% vs 0; P = .006). Child survivors were more likely to develop grade 3 to 4 growth retardation and endocrine insufficiency (3.0% vs 0.3%; P = .014).Child patients with NPC achieved significantly better survival outcomes but fewer late toxicities than adult patients. However, we should pay great attention to growth problems of child survivors.

Background and aims High serum hepatocyte growth factor (HGF) levels increase the risk of ischemic stroke and are probably associated with outcomes after ischemic stroke. However, it remains unclear whether the association between HGF and ischemic stroke prognosis is modified by blood lipid status. Methods and results Data were derived from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), and we measured baseline serum HGF levels in 3027 ischemic stroke patients. The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 2 years after ischemic stroke. Blood lipid status could modify association between HGF and ischemic stroke prognosis (Pinteraction = 0.002). After multivariate adjustment, the odds ratios of primary outcome associated with the highest tertile of HGF were 2.13 (95% CI, 1.45–3.14; Ptrend Conclusions There was a modified effect of blood lipid status on the association between serum HGF and ischemic stroke prognosis. Elevated serum HGF was associated with outcomes in ischemic stroke patients with dyslipidemia, especially low HDL-C. Further studies are warranted to replicate our findings and clarify the potential biological mechanisms.

Background As a key enzyme of natriuretic peptides system playing an integral role in energy homeostasis, furin may be a potential contributor to obesity. However, the association between furin and obesity has been scarcely studied. This study aims to examine the prospective association between serum furin and abdominal obesity. Methods Waist circumference (WC) was measured twice 4 years apart for a total of 892 Chinese adults free of abdominal obesity at baseline. Abdominal obesity was defined as WC over 85 cm for men and as WC over 80 cm for women. A Cox proportional hazard model was constructed to examine the association of baseline serum furin with incident abdominal obesity. Results After an average 4 years of follow-up, 184 participants developed new abdominal obesity. Baseline serum furin was significantly associated with dynamic body weight during follow-up (β=−0.593, p=0.003). Participants with a higher level of serum furin at baseline were less likely to develop new abdominal obesity compared with those with a lower level of serum furin (HR=0.81, 95% CI 0.67 to 0.97). Conclusions A lower level of serum furin predicts a higher risk of developing future abdominal obesity in Chinese adults. Furin deficiency may be a contributor to abdominal obesity but still needs further investigations.