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To identify the typical pattern of changes of vestibular-evoked myogenic potentials (VEMPs) and explore the relationship between VEMPs and the anthropometry factors in patients with obstructive sleep apnea (OSA).Patients diagnosed as OSA after overnight polysomnography (PSG) tests were enrolled as the study group. Healthy volunteers were recruited as the control group. Anthropometry data of the body shape and VEMPs results were collected completely. The correlation analysis was conducted among those parameters.Forty-nine patients with OSA who were diagnosed in the Therapy Center of Sleep-disordered Breathing in our hospital and sex- and age-matched healthy controls as well. Significant changes in ocular and cervical VEMPs (oVEMP and cVEMP) in the study group were observed, which were reduced response rates, elevated thresholds, decreased amplitudes, and prolonged first wave latencies. In oVEMP, the first wave (n1) latency was significantly correlated with weight, body mass index (BMI), neck circumference, waist circumference, hip circumference, and apnea hypopnea index (AHI). In a tentative application, combined use of BMI and oVEMP n1 latency increased the detection rate during OSA screening prior to PSG.OSA can negatively affect function of otolithic organs and their pathways. The first wave latency of the VEMPs waveform may be another important parameter to define peripheral nervous system lesions caused by systemic diseases as OSA.

ImportanceMild thyroid-associated ophthalmopathy (TAO) negatively impacts quality of life, yet no clinical guidelines for its treatment are available. Existing evidence supports the use of doxycycline in treating mild TAO.ObjectiveTo evaluate the short-term (12 weeks) efficacy of doxycycline in treating mild TAO.Design, Setting, and ParticipantsIn this placebo-controlled multicenter randomized double-masked trial, 148 patients were assessed for eligibility. After exclusions (patients who were pregnant or lactating, had an allergy to tetracyclines, or had uncontrolled systematic diseases), 100 patients with mild TAO (orbital soft tissue affected mildly) at 5 centers in China were enrolled from July 2013 to December 2019 and monitored for 12 weeks.InterventionsParticipants were randomly assigned 1:1 to receive doxycycline (50 mg) or placebo once daily for 12 weeks.Main Outcomes and MeasuresThe primary outcome was the rate of improvement at 12 weeks compared with baseline assessed by a composite indicator of eyelid aperture (reduction ≥2 mm), proptosis (reduction ≥2 mm), ocular motility (increase ≥8°), and Graves ophthalmopathy-specific quality-of-life (GO-QOL) scale score (increase ≥6 points). Adverse events were recorded.ResultsA total of 50 participants were assigned to doxycycline and 50 to placebo. The mean (SD) age was 36.7 (9.1) years; 75 participants (75.0%) were female and 100 (100.0%) were Asian. Medication compliance was checked during participant interviews and by counting excess tablets. At week 12, the improvement rate was 38.0% (19 of 50) in the doxycycline group and 16.0% (8 of 50) in the placebo group (difference, 22.0%; 95% CI, 5.0-39.0; P = .01) in the intention-to-treat population. The per-protocol sensitivity analysis showed similar results (39.6% [19 of 48] vs 16.0% [8 of 50]; difference, 23.6%; 95% CI, 6.4-40.8; P = .009). No adverse events other than 1 case of mild gastric acid regurgitation was recorded in either group.Conclusions and RelevanceThe results of this study indicate that oral doxycycline, 50 mg daily, resulted in greater improvement of TAO-related symptoms at 12 weeks compared with placebo in patients with mild TAO. These findings support the consideration of doxycycline for mild TAO but should be tempered by recognizing the relatively short follow-up and the size of the cohort.Trial RegistrationClinicalTrials.gov Identifier: NCT02203682

Background. Asthma significantly impacts human life and health as a chronic disease. Traditional treatments for asthma have several limitations. Artificial intelligence aids in cancer treatment and may also accelerate our understanding of asthma mechanisms. We aimed to develop a new clinical diagnosis model for asthma using artificial neural networks (ANN). Methods. Datasets (GSE85566, GSE40576, and GSE13716) were downloaded from Gene Expression Omnibus (GEO) and identified differentially expressed CpGs (DECs) enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Random forest (RF) and ANN algorithms further identified gene characteristics and built clinical models. In addition, two external validation datasets (GSE40576 and GSE137716) were used to validate the diagnostic ability of the model. Results. The methylation analysis tool (ChAMP) considered DECs that were up-regulated ( n =121) and down-regulated ( n =20). GO results showed enrichment of actin cytoskeleton organization and cell-substrate adhesion, shigellosis, and serotonergic synapses. RF (random forest) analysis identified 10 crucial DECs (cg05075579, cg20434422, cg03907390, cg00712106, cg05696969, cg22862094, cg11733958, cg00328720, and cg13570822). ANN constructed the clinical model according to 10 DECs. In two external validation datasets (GSE40576 and GSE137716), the Area Under Curve (AUC) for GSE137716 was 1.000, and AUC for GSE40576 was 0.950, confirming the reliability of the model. Conclusion. Our findings provide new methylation markers and clinical diagnostic models for asthma diagnosis and treatment.

Melanoma is becoming increasingly common worldwide, with high rates of transformation into malignancy compared to other skin lesions. The prognosis of patients with melanoma at an advanced stage is highly unsatisfying despite the development of immunotherapy, target therapy, or combinative therapy. The major barrier to exploiting immune checkpoint therapies and achieving the best benefits clinically is resistance that can easily develop if regimens are not selected appropriately. In this study, we investigated the possibility of using immune-related genes to predict patient survival and their responses to immune checkpoint blocker therapies with the expression profiles available at The Cancer Genome Atlas (TCGA) Program plus expression data from the Gene Expression Omnibus (GEO) for validation. A five gene signature that is highly correlated with the local infiltration of cytotoxic lymphocytes in the tumor microenvironment was identified, and a scoring model was developed with stepwise regression after multivariate Cox analyses. The score calculated strongly correlates with Breslow depth, and this model effectively predicts the prognosis of patients with melanoma, whether primary or metastasized. It also depicts the heterogenous immune-related nature of melanoma by revealing different predicted responses to immune checkpoint blocker therapies through its correlation to tumor immune dysfunction and exclusion (TIDE) score.

The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients.This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients.Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10-16, 16-30, and 30-40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10-16, 16-25, 25-30, and 30-40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10-40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10-24 and 24-40 kg, respectively.This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients.

Lung cancer is the leading cause of cancer death worldwide. Data on the effectiveness of one-off low-dose CT (LDCT) in reducing lung cancer mortality and all-cause mortality are needed to inform screening programmes in countries with limited medical resources. We aimed to evaluate the effectiveness of one-off LDCT screening in the early detection of lung cancer in China.A multicentre, population-based, prospective cohort study was done in 12 cities of eight provinces across China, recruiting individuals aged 40-74 years who were asymptomatic for lung cancer with no lung cancer history. Participants were classified as at high risk or low risk of lung cancer using a sex-specific risk score that incorporated cigarette smoking, level of physical activity, occupational exposures, history of chronic respiratory diseases, family history of lung cancer, diet, and passive smoking (women only). Participants at high risk were invited for a one-off LDCT scan and were classified into screened and non-screened groups on the basis of whether or not they had the scan. Lung cancer incidence density, lung cancer mortality, and all-cause mortality were calculated for the screened and non-screened groups. The effectiveness of a one-off LDCT scan was evaluated by a comparison of the screened and non-screened groups in terms of lung cancer mortality and all-cause mortality in the period from cohort entry until administrative censoring (June 20, 2020). Inverse probability weighting was adopted to account for potential imbalanced factors between the two groups and Cox proportional hazards model was used to estimate the weighted associations between mortality and one-off LDCT scans.Between Feb 19, 2013, and Oct 31, 2018, 1 032 639 individuals were assessed for eligibility. 1 016 740 participants were enrolled in the study, of whom 3581 had a lung cancer diagnosis after a median follow-up of 3·6 years (IQR 2·8-5·1). Among the 223 302 participants at high risk, 79 581 (35·6%) had an LDCT scan (screened group) and 143 721 (64·4%) did not (non-screened group). After inverse probability weighting, lung cancer incidence density was 47·0% higher (hazard ratio 1·47 [95% CI 1·27-1·70]; p0·0001), lung cancer mortality was 31·0% lower (0·69 [95% CI 0·53-0·92]; p=0·010) and all-cause mortality was 32·0% lower (0·68 [0·57-0·82]; p0·0001) for participants in the screened group compared with those in the non-screened group.One-off LDCT screening was associated with significantly lower lung cancer mortality and all-cause mortality in a large population in China. Our results point to the promise of one-off LDCT screening in countries with limited medical resources. Further studies are needed to explore interactions by subgroup-including sex, age, smoking status, and economic status-to develop population-specific screening strategies.Ministry of Finance and National Health Commission of the People's Republic of China.For the Chinese translation of the abstract see Supplementary Materials section.

The present study aims to investigate whether malnutrition defined by the Global Leadership Initiative in Malnutrition (GLIM) criteria using hand-grip strength (HGS) adequately predict postoperative complications and long-term survival in patients underwent radical gastrectomy for gastric cancer in a similar manner to GLIM-defined malnutrition using skeletal muscle index (SMI).Patients who underwent radical gastrectomy for gastric cancer from August 2014 to June 2019 were included in this study. Clinical data were prospectively collected. Malnutrition was diagnosed based on the two-step approach following the GLIM criteria. Skeletal muscle mass was assessed using SMI based on abdominal computed tomography (CT) scans, or assessed using HGS.A total of 1359 patients were included in this study, in which 36.2% of the patients were at risk of malnutrition (Nutritional Risk Screening 2002 scores ≥3). The incidence of malnutrition was 28.2% and 27.5% using SMI and HGS, respectively. There was a high agreement between the two criteria of malnutrition (kappa = 0.863, P 0.001). Both of the two criteria of malnutrition were independently associated with postoperative complications (SMI-GLIM, P = 0.041; HGS-GLIM, P = 0.023), overall survival (P 0.001, both), and disease-free survival (P 0.001, both), with similar odds ratio or hazard ratio after adjusting for the same confounding variables. HGS-GLIM malnutrition (P = 0.046) but not SMI-GLIM malnutrition (P = 0.270) was associated with a higher incidence of severe complications.GLIM criteria using HGS is a useful tool to diagnose malnutrition and has a similar or even better predictive value for postoperative complications and long-term survival after radical gastrectomy for gastric cancer compared with GLIM criteria using SMI.

Detecting and measuring intraluminal thrombus has prognostic and therapeutic implications for stroke patients.To investigate the feasibility of 3D isotropic high-resolution T1w-CUBE imaging to detect and measure intraluminal thrombus in stroke patients.Retrospective.A total of 93 patients with acute (N = 39) and subacute (N = 54) stroke.A 3.0 T/spin-echo echo-planar diffusion-weighted imaging (DWI), high-resolution T1w-CUBE imaging and 3D flow compensated gradient-echo susceptibility-weighted imaging (SWI).Data assessment was performed by three neuroradiologists with 11, 13, and 20 years of clinical experience. The accuracy of T1W-CUBE and SWI in diagnosing thrombosis was compared by using digital subtraction angiography (DSA) as the reference. For thrombus length measurement, the image quality of proximal and distal thrombus of T1w-CUBE images was first evaluated with a 4-point rating system. Then, the proximal and distal positions to lesions were determined on T1w-CUBE images and compared with those from DSA acquired during endovascular reperfusion therapy. If comparable both locations were found between CUBE and DSA, CUBE imaging can thus be considered for accurate measurement of thrombus length.Fleiss' Kappa; the area under the receiver operating characteristic (ROC) curve (AUC); Pearson's chi-squared test with Yates' continuity correction.Moderate-to-good interobserver agreements were validated with all Kappa coefficients higher than 0.40 in thrombus diagnosis and measurement. CUBE imaging showed higher clinical efficacy than SWI (AUC: 0.966 vs. 0.850) in thrombus diagnosis. Additionally, high quality of CUBE imaging was confirmed with 3 or 4 points rated by all three observers. Compared to intraoperative DSA, T1w CUBE showed consistent proximal and distal positions of thrombi in 16 of the 18 patients, validating the accuracy of T1w-CUBE in measuring thrombus length.T1w-CUBE imaging has potential to facilitate diagnosis and measurement of intraluminal thrombus.4 TECHNICAL EFFICACY: Stage 2.

Aims. The present study is aimed at exploring the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on weight in type 2 diabetes mellitus (T2DM) and therapeutic regimen recommendations. Methods. 20,019 patients with T2DM were enrolled. The maximal effect ( E max ) models, whose evaluation index was change rate of body weight from baseline value, were used to analyze data using nonlinear mixed effect modeling (NONMEM). Results. For SGLT-2 inhibitors, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin, the E max , and treatment duration to reach half of the maximal effects (ET50) were -3.72% and 3.35 weeks, -5.59% and 16.8 weeks, -2.84% and 3.42 weeks, -3.43% and 3.09 weeks, -3.04% and 4.38 weeks, and -2.45% and 3.16 weeks, respectively. In addition, for T2DM patients, 100 mg/day canagliflozin needs to be taken 13.4 weeks for the plateau of effect on weight; 10 mg/day empagliflozin needs to be taken 67.2 weeks for the plateau of effect on weight; 5 mg/day ertugliflozin needs to be taken 13.68 weeks for the plateau of effect on weight; 50 mg/day ipragliflozin needs to be taken 12.36 weeks for the plateau of effect on weight; 2.5 mg/day luseogliflozin needs to be taken 17.52 weeks for the plateau of effect on weight; 20 mg/day tofogliflozin needs to be taken 12.64 weeks for the plateau of effect on weight. Conclusions. This was the first study to explore effects of SGLT-2 inhibitors on weight in T2DM; meanwhile, the optimum dosages and treatment durations on weight from canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin were recommended, respectively.

Background Social distancing and “stay-at-home” orders are essential to contain the coronavirus outbreak; however, there are growing concerns about physical and other mental distress in older people. Apart from quantitative data, their feelings, thoughts, and experience are essential to inform the implementation of patient-centered health care policy. Aim This study explained the psychosocial effects of COVID-19 on Hong Kong Chinese older people. Design and Setting This was a qualitative study. Twenty-three participants aged between 63 and 86 were recruited in primary care through purposive sampling. Method Semi-structured in-depth telephone interviews were conducted to explore participants’ experience during the COVID-19 pandemic. Grounded theory was used to analyze the data. Results Three themes, nine subthemes, and 24 quotes were identified. The 3 themes included the psychological response of fear, annoyance, and worrisome; social isolation leading to loneliness and physical exhaustion; and the coping strategies in adversity. Fear was the major emotional response, which was not entirely explained by the uncertainty of the disease, but also the embedded routines norms and values. Loneliness was aggravated by the depleted family and community support. Physical distancing had intensified ones physical demand on self-care, especially among those with comorbid illnesses. The use of digital tools and telecommunications maintained the social connection, but the overexposure had led to a vicious cycle of anxiety and distress. Conclusion Self-isolation has disproportionately affected older individuals whose only social contact is out of the home. Online technologies can be harnessed to provide social support networks and a sense of belonging, but its adaptive and positive uses should be encouraged. Interventions can also involve more frequent telephone contact with significant others, close family and friends, voluntary organizations, or health-care professionals, or community outreach teams. Enhancing the values of older people’s in calamity through active engagement may also potentially reduce the detrimental effect of social isolation.

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) act as tumor promoters or suppressors in various types of cancer. Previous investigations suggest that ceramide synthase 6 (CERS6) antisense RNA 1 (CERS6-AS1) acts as an oncogene in breast cancer; however, its role in colorectal cancer is unknown. This study aimed to explore the molecular mechanism of CERS6-AS1 in colorectal cancer. Gene expression in colorectal cancer was examined using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The viability and proliferation of colorectal cancer cells were measured by Cell Counting Kit-8 assays and colony formation assays. The migratory and invasive capacities of the colorectal cancer cells were assessed by Transwell assay. Cell stemness was examined by sphere-formation assay. Mechanistically, RNA pull-down assays, RNA immunoprecipitation assays, and luciferase reporter assays were performed to explore the relationship among CERS6-AS1, miR-15b-5p and spectrin beta, non-erythrocytic 2 (SPTBN2). Moreover, a xenograft tumor model was established to investigate the role of CERS6-AS1 in vivo. We found that CERS6-AS1 and SPTBN2 were highly expressed in colorectal cancer tissues and cells. CERS6-AS1 depletion inhibited cell viability, proliferation, migration, and invasion; the epithelial-mesenchymal transition process and stemness. It suppressed xenograft tumor growth in colorectal cancer. Moreover, SPTBN2 levels were positively regulated by CERS6-AS1 and negatively regulated by miR-15b-5p in colorectal cancer cells. Rescue assays revealed that SPTBN2 reversed the inhibitory effect of CERS6-AS1 deficiency on the malignant behaviors of colorectal cancer cells. Overall, the lncRNA CERS6-AS1 facilitates malignant phenotypes of colorectal cancer cells by targeting miR-15b-5p to upregulate SPTBN2.

Piwi-interacting RNAs (piRNAs) are a class of short chain noncoding RNAs that are constituted by 26-30 nucleotides (nt) and can couple with PIWI protein family. piRNAs were initially described in germline cells and are believed to be critical regulators of the maintenance of reproductive line. Increasing evidence has extended our perspectives on the biological significance of piRNAs and indicated that they could still affect somatic gene expression through DNA methylation, chromatin modification and transposon silencing, etc. Many studies have revealed that the dysregulation of piRNAs might contribute to diverse diseases through epigenetic changes represented by DNA methylation and chromatin modification. In this review, we summarized piRNA/PIWI protein-mediated DNA methylation regulation mechanisms and methylation changes caused by piRNA/PIWI proteins in different diseases, especially cancers. Since DNA methylation and inhibitory chromatin marks represented by histone H3 lysine 9 (H3K9) methylation frequently cooperate to silence genomic regions, we also included methylation in chromatin modification within this discussion. Furthermore, we discussed the potential clinical applications of piRNAs as a new type promising biomarkers for cancer diagnosis, as well as the significance of piRNA/PIWI protein-associated methylation changes in treatment, providing disparate insights into the potential applications of them.

Thyroid cancer (TC) has increased globally, with a prominent increase in small, papillary thyroid cancers. PEST-containing nuclear protein (PCNP), a nuclear protein, has been found to be associated with human cancers in recent years. However, the role and molecular mechanism of PCNP in thyroid cancer remain underexplored. In the present study, the results showed that the expression levels of PCNP in human thyroid tissues were higher than those in adjacent non-tumor tissues. Overexpression of PCNP reduced the proliferation, migration, and invasion of human thyroid cancer cells and down-regulation of PCNP showed reverse effects. In addition, PCNP regulated cell cycle arrest through modifications in the expression of cell cycle regulating genes and PCNP affected apoptosis via activation of ERK/JNK/p38 pathway in thyroid cancer cells. Moreover, PCNP overexpression promoted autophagy by reducing the expression levels of Wnt/β-catenin pathway in TC cells, however, PCNP knockdown had opposite effects. Furthermore, PCNP overexpression reduced the growth of xenografted human thyroid cancer, whereas PCNP knockdown showed opposite trends. In conclusion

Understanding the mechanisms underlying phenotypic innovation is a key goal of comparative genomic studies. Here, we investigated the evolutionary landscape of lineage-specific accelerated regions (LinARs) across 49 primate species. Genomic comparison with dense taxa sampling of primate species significantly improved LinAR detection accuracy and revealed many novel human LinARs associated with brain development or disease. Our study also yielded detailed maps of LinARs in other primate lineages that may have influenced lineage-specific phenotypic innovation and adaptation. Functional experimentation identified gibbon LinARs, which could have participated in the developmental regulation of their unique limb structures, whereas some LinARs in the Colobinae were associated with metabolite detoxification which may have been adaptive in relation to their leaf-eating diet. Overall, our study broadens knowledge of the functional roles of LinARs in primate evolution.

Objective To explore the application value of breast cancer tumor markers tissue polypeptide specific antigen (TPS), carbohydrate antigen 15-3 (CA15-3), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125) detection alone or in combination for the monitoring of distant metastasis of breast cancer. Method The clinical data of 389 female breast cancer patients admitted to Tianjin Medical University Cancer Institute and Hospital from January 2016 to March 2017 were retrospectively analyzed. Serum levels of TPS, CA125, CA15-3, and CEA were compared to analyze their significance in prediction distant metastasis of breast cancer. The patients were divided into the distant metastatic group and the non-metastatic group according to whether the patients had distant metastasis. The non-metastatic group was divided into the control group and the occult metastasis group according to whether distant metastases occurred in 3 years after treatment. Result The receiver operating characteristic curve analysis revealed that all four markers had the diagnostic value in distant metastasis of breast cancer (AUCTPS = 0.754, AUC15-3 = 0.821, AUCCEA = 0.755, AUCCA125 = 0.651) and in occult metastasis in 3 years after treatment (AUCTPS = 0.751, AUC15-3 = 0.744, AUCCEA = 0.725, AUCCA125 = 0.661). To estimate whether the discrimination ability could be improved by marker panels, we established marker panels composed of TPS, CA125, CA15-3, and CEA. To discriminate distant metastasis from non-distant metastasis, the diagnostic ability of different panels composed of TPS, CA125, CA15-3 and CEA did not show significant difference compared with single CA15-3 (P > 0.05). To discriminate occult metastasis from the control group, no significant difference was shown in AUC between marker panels and single marker (P > 0.05). However, the sensitivity was improved when the marker-panels were used overall. Conclusion All tumor markers have abilities in prediction of distant metastasis of breast cancer. The combined detection of the markers is more valuable than using single tumor marker in improving sensitivity. Two markers' panels are more suitable for the prediction of distant metastasis of breast cancer than three or four makers' panels with the similar sensitivity and AUC.

Vascular calcification is highly prevalent in chronic kidney disease (CKD), and is characterized by transdifferentiation from contractile vascular smooth muscle cells (VSMCs) into an osteogenic phenotype. However, no effective and therapeutic option to prevent vascular calcification is yet available. Dihydromyricetin (DMY), a bioactive flavonoid isolated from Ampelopsis grossedentata, has been found to inhibit VSMCs proliferation and the injury-induced neointimal formation. However, whether DMY has an effect on osteogenic differentiation of VSMCs and vascular calcification is still unclear. In the present study, we sought to investigate the effect of DMY on vascular calcification in CKD and the underlying mechanism. DMY treatment significantly attenuated calcium/phosphate-induced calcification of rat and human VSMCs in a dose-dependent manner, as shown by Alizarin Red S staining and calcium content assay, associated with down-regulation of osteogenic markers including type I collagen (COL I), Runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2) and osteocalcin (OCN). These results were further confirmed in aortic rings ex vivo. Moreover, DMY ameliorated vascular calcification in rats with CKD. Additionally, we found that AKT signaling was activated during vascular calcification, whereas significantly inhibited by DMY administration. DMY treatment significantly reversed AKT activator-induced vascular calcification. Furthermore, inhibition of AKT signaling efficiently attenuated calcification, which was similar to that after treatment with DMY alone, and DMY had a better inhibitory effect on calcification as compared with AKT inhibitor. The present study demonstrated that DMY has a potent inhibitory role in vascular calcification partially by inhibiting AKT activation, suggesting that DMY may act as a promising therapeutic candidate for patients suffering from vascular calcification.

Prion disease (PrD) and Parkinson's disease (PD) are neurodegenerative diseases characterized by aggregation of misfolded proteins in brain tissues, including protease-resistant prion protein (PrPSc) in PrD and α-synuclein in PD. In recent years, overlap of these two proteins has attracted increased attention, and cross-seeding of prion proteins by aggregated α-synuclein has been proposed. However, the changes in α-synuclein after prion infection are still unclear. In this study, we showed that α-synuclein expression was significantly decreased in the brains of prion-infected rodent models, in the SMB-S15 cell line, which exhibits persistent prion replication, and in the brains of humans with PrDs. Meanwhile, α-synuclein phosphorylated at serine 129(p(S129)-α-synuclein) was significantly increased in the brains of scrapie-infected mice and prion-infected SMB-S15 cells. The increased p(S129)-α-synuclein colocalized with GFAP- and NeuN-positive cells in the brains of scrapie-infected mice. p(S129)-α-synuclein was also observed in the cytoplasm of SMB-S15 and HEK-293 cells transiently expressing an abnormal form of prion protein (Cyto-PrP). Molecular interactions between PrP and α-synuclein were detected in recombinant proteins, normal and prion-infected brain tissues, and cultured cells. The increased p(S129)-α-synuclein colocalized with PrP signals from prion-infected SMB-S15 and HEK-293 cells expressing Cyto-PrP. Moreover, increased morphological colocalization of p(S129)-α-synuclein with mitochondrial markers was also detected in the two cell types. Our results indicate that prion replication and accumulation in cells and brains induce hyperphosphorylation of α-synuclein, particularly at S129, which may aggravate mitochondrial damage and facilitate α-synuclein aggregation in the central nervous system tissues from PrDs.

To analyze the preservation effect and related influencing factors of human peripheral blood mononuclear cells under serum-free condition at 4 ℃.Human peripheral blood mononuclear cells were isolated by density gradient centrifugation, and stored at 4 ℃ under different cell concentrations, supplemented with human serum albumin, and glucose. The cell viability, total cell number, viable cell number and cell phenotype were detected during preservation of 72 h.With the prolongation of storage time, the number of human peripheral blood mononuclear cells gradually decreased(The cell density of (1-2)×10影响人外周血单个核细胞4 ℃保存效果的因素分析.分析4 ℃无血清条件下人外周血单个核细胞保存效果及其相关影响因素.采用密度梯度离心法分离人外周血单个核细胞，使用不同细胞密度、添加人血清白蛋白、葡萄糖等条件对其进行4 ℃保存，并检测保存72 h内细胞的存活率、细胞数量、活细胞数量和细胞表型.随保存时间延长，人外周血单个核细胞数量逐步下降((1-2)×10

Peer reviewed: True, Acknowledgements: The authors would like to thank the Illness Challenge Foundation for their assistance and coordination in distributing questionnaires., BACKGROUND: A considerable proportion of rare disease patients decide to migrate to access a definitive diagnosis or appropriate care, which could affect their quality of life in a long term. OBJECTIVE: To compare quality of life (QoL) between migrants and residents and explore the possible mechanism of how migration influence the QoL among rural and urban adults with rare diseases, respectively. METHODS: A cross-sectional study at national level was conducted in a study sample of 1,150 adult patients in China. Migration was defined as being away from one's original place of residence for at least 12 months. Patients who remained in their place of residence in the past 12 months ("resident") were treated as a comparison group for "migrants". Original area of residence (rural vs. urban) for both residents and migrants was used for comparison. The brief version of the World Health Organization Quality of Life instrument was used to measure QoL. Multiple linear regression analyses were adopted to assess the direct association between migration status and QoL after controlling for the confounders that affect QoL. The indirect associations between migration status and QoL, mediated by potential mediators including number of family members living together, individual income, catastrophic health expenditure, and social support, were estimated using the mediation model. RESULTS: Among the group of rural participants, migration was directly associated with physical QoL (β = 5.07, 95% CI 2.01-8.13) and environmental QoL (3.95, 1.37-6.53), indirectly associated with physical QoL (0.58, 0.05-1.28) and social QoL (0.50, 0.01-1.16) via individual income, and also indirectly associated with environmental QoL (-0.47, -1.12 to -0.50) via tangible support. On the other hand, neither direct nor indirect associations of migration with four domain scores of QoL were significant among the group of urban participants. CONCLUSION: Among rural adults with rare diseases, migration was found to have positive direct effect on physical and environmental QoL, positive indirect effect on physical and social QoL through increased individual income, and negative indirect effect on environmental QoL via reduced tangible support. By contrast, neither direct nor indirect associations of migration with QoL were significant among the group of urban participants.

The Forkhead box class O proteins (FOXOs) family consists of highly conserved transcription factors, including FOXO1, FOXO3, FOXO4 and FOXO6. Each member of the FOXOs family is ubiquitously expressed and involved in regulating many biological activities such as tumor cell proliferation, apoptosis, migration and oxidative stress. The activity of FOXOs is mainly regulated by post-translational modification, and its inactivation is mainly mediated by the over-activation of its upstream modifying enzymes, which provides a possibility to use drugs to recover its activity. It is worth noting that FOXOs can not only inhibit, but also promote the occurrence and development of human tumors due to the complex effects of FOXOs. This review will summarize the structure and activity regulation of FOXOs, and discuss their tumor inhibiting effects by limiting cell proliferation and inducing apoptosis, as well as their tumor promoting effects by maintaining cell homeostasis, promoting metastasis and inducing drug resistance, so as to provide new ideas for the pathological research of related diseases and open up new ways to promote broader prevention and treatment strategies.

The evolutionary and functional features of RNA editing are well studied in mammals, cephalopods, and insects, but not in birds. Here, we integrated transcriptomic and whole-genomic analyses to exhaustively characterize the expansive repertoire of adenosine-to-inosine (A-to-I) RNA editing sites (RESs) in the chicken. In addition, we investigated the evolutionary status of the chicken editome as a potential mechanism of domestication. We detected the lowest editing level in the liver of chickens, compared to muscles in humans, and found higher editing activity and specificity in the brain than in non-neural tissues, consistent with the brain's functional complexity. To a certain extent, specific editing activity may account for the specific functions of tissues. Our results also revealed that sequences critical to RES secondary structures remained conserved within avian evolution. Furthermore, the RNA editome was shaped by purifying selection during chicken domestication and most RESs may have served as a selection pool for a few functional RESs involved in chicken domestication, including evolution of nervous and immune systems. Regulation of RNA editing in chickens by adenosine deaminase acting on RNA (ADAR) enzymes may be affected by non-ADAR factors whose expression levels changed widely after目前有关RNA编辑在哺乳动物、头足类动物和昆虫等中的进化和功能研究已有了很好的进展，但在鸟类中仍存在很大空白。该研究中，通过整合转录组学和全基因组学分析，我们详细地描绘了鸡中腺嘌呤核苷转为次黄嘌呤核苷（Adenosine-to-inosine, A-to-I）的RNA编辑模式的位点（RNA editing sites, RESs）图谱。此外，我们还研究了RNA编辑在家鸡驯化过程中可能的作用机制。我们发现，鸡肝脏的编辑水平最低，这与已报道的人的肌肉编辑水平最低的结论不同。而鸡大脑的编辑活性和特异性均显著高于非神经组织，这与大脑的功能复杂性一致，因为在一定程度上，组织特异的编辑活性或许可以为其特定的功能作出解释。同时，我们的研究结果还显示，影响RESs二级结构形成的关键序列在鸟类进化过程中是保守的，并在家鸡的驯化过程中受到负选择。大多数RESs可能构成一个选择池，用以筛选出在驯化过程起功能性作用的少数RESs，譬如参与神经系统和免疫系统的进化等。最后，我们的结果也揭示，在鸡里，RNA编辑酶ADARs对RNA编辑的调控可能受到非ADAR（non-ADAR）因子的影响，这些因子的表达水平在ADAR基因被敲除后发生了显著的变化。总而言之，我们提供了鸡RESs和non-ADAR编辑调控因子的综合列表，它们或将促进我们对RNA编辑在动物功能和进化中的可能作用的理解。.

Background Cervical squamous cell carcinoma (CESC) is the most common histological type of cervical cancer which is the major cause of death in women worldwide. Although squamous cell carcinoma antigen (SCC-Ag) is widely used to detect CESC, it is not sensitive and specific enough to predict the disease. Methods We investigated serum CXC motif chemokine 10 (CXCL10) as potential diagnostic biomarker in detecting CESC in this study. Serum levels of CXCL10 and SCC-Ag were measured by ELISA or automated immunoassay in 345 participants, including 189 patients with different stages of CESC, 75 patients with cervical intraepithelial neoplasia, and 81 healthy individuals. Performances of CXCL10 and SCC-Ag as single biomarkers were analyzed by the ROC curves. The changes of serum levels of CXCL10 and SCC-Ag in 10 longitudinal followed-up CESC patients with partial response (PR) during chemoradiotherapy or chemotherapy were evaluated. Results The two markers showed similar diagnostic capacity in distinguishing both CESC early stage from healthy controls (AUCCXCL10 = 0.740, AUCSCC-Ag = 0.710) and all CESC from healthy controls (AUCCXCL10 = 0.775, AUCSCC-Ag =0.793). Moreover, CXCL10 showed ability in distinguishing cervical intraepithelial neoplasia from healthy control (AUCCXCL10 = 0.727) and cervical cancer SCC-Ag-negative from healthy control. (AUCCXCL10 = 0.739). The combination of CXCL10 and SCC-Ag displayed significant improvement of AUCs than individual SCC-Ag or CXCL10 in the analysis groups (healthy vs all cervical cancer, healthy vs cervical cancer early stage). The AUCs were improved to 0.877 (AUCSCC-Ag = 0.793, P P P P = 0.013), whose consistent and inconsistent frequency with the response were the same as serum SCC-Ag levels. Conclusions The results indicated that CXCL10 is a potential serum biomarker complementing SCC-Ag in prediction of CESC. CXCL10 showed ability in the diagnosis of SCC-Ag negative CESC and the combination of CXCL10 and SCC-Ag inhibited improved performance compared with SCC-Ag alone.

Introduction Berberine (BBR), as one of the outstanding representatives of isoquinoline alkaloids, has been used as an antibacterial drug for a long time in China since ancient times. Currently, a large number of studies have been reported that berberine has a wide spectrum of pharmacological activities, such as anti-tumor, anti-inflammatory, hypoglycemic, hypolipidemic, anti-obesity, and the like. Areas covered This review systematically discussed important patents on berberine and berberine derivatives in terms of pharmacological activity between 2016 and 2020. These patents were mainly searched through the European Patent Office database and Web of Science. These berberine patents (~41) cover a wide range of applications, mainly including antitumor, anti-inflammatory, antibacterial, anti-metabolic disorder, and other newly reported pharmacological activities. Expert opinion Berberine is an important lead compound with great potential for optimization in drug development. However, there is a lack of research related to the biomolecular targets of BBR, which directly restricts the development of berberine in the pharmaceutical field. The problems involved with poor bioavailability and cytotoxicity are also worth considering in the development of berberine-based drugs. Accordingly, the increasing number of patents involving biomolecular targets in BBR's patent applications will be published as its related pharmacological mechanisms are further deciphered.

Human genetic prion diseases (gPrDs) are directly associated with mutations and insertions in the PRNP (Prion Protein) gene. We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020. Nineteen different subtypes were identified and gPrDs accounted for 10.9% of all diagnosed PrDs within the same period. Some subtypes of gPrDs showed a degree of geographic association. The age at onset of Chinese gPrDs peaked in the 50–59 year group. Gerstmann–Sträussler–Scheinker syndrome (GSS) and fatal familial insomnia (FFI) cases usually displayed clinical symptoms earlier than genetic Creutzfeldt–Jakob disease (gCJD) patients with point mutations. A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients. None of the E196A gCJD patients reported a family history. The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD (sCJD). EEG examination was not sensitive for gPrDs. sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients. CSF 14-3-3 positivity was frequently detected in gCJD patients. Increased CSF tau was found in more than half of FFI and T188K gCJD cases, and an even higher proportion of E196A and E200K gCJD patients. 63.6% of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC. GSS and FFI cases had longer durations than most subtypes of gCJD. This is one of the largest studies of gPrDs in East Asians, and the illness profile of Chinese gPrDs is clearly distinct. Extremely high proportions of T188K and E196A occur among Chinese gPrDs; these mutations are rarely reported in Caucasians and Japanese.

Background In China, coronary artery abnormalities (CAAs) secondary to Kawasaki disease (KD) tend to have an increased occurrence. We hypothesize that Chinese children with KD may possess several unique CAA risks, and the predictive efficacy of multiple scoring systems in Chinese patients are still to be further studied. Methods Two hundred and three KD patients were recruited. Using multivariable analysis, independent predictors of CAAs were combined into a scoring system. Subsequently, CAA risks of our patients were evaluated by the newly established scoring system and eight other published scoring systems. Results Seventeen (8.37%) KD patients were identified as CAAs. The newly established scoring system contained the following 5 independent predictors: days of illness at initial treatment ≥7, redness and swelling of extremities, hematocrit ≤33%, percentage of monocytes ≥8.89%, and procalcitonin ≥0.5 ng/mL. The AUC value of newly established scoring system was 0.685 with a sensitivity of 41.18% and a specificity of 84.41%, higher than Harada score, Egami score, Kobayashi score, Sato score, San Diego score, Formosa score, and Tang score, whereas lower than Hua score. Conclusions Days of illness at initial treatment ≥7 and procalcitonin are unique predictors of CAAs in newly established scoring system. Taking into account different identification criteria and analytical methodologies, there is still some heterogeneity among different scoring systems. Impact The newly established scoring system contains the five independent predictors. Days of illness at initial treatment ≥7 and PCT are unique predictors of CAAs in our study, compared with 8 other systems. The AUC value of newly established scoring system is 0.685, similar to Hua score. There is some heterogeneity among different scoring systems.

Donkeys transformed human history as essential beasts of burden for long-distance movement, especially across semi-arid and upland environments. They remain insufficiently studied despite globally expanding and providing key support to low- to middle-income communities. To elucidate their domestication history, we constructed a comprehensive genome panel of 207 modern and 31 ancient donkeys, as well as 15 wild equids. We found a strong phylogeographic structure in modern donkeys that supports a single domestication in Africa similar to 5000 BCE, followed by further expansions in this continent and Eurasia and ultimately returning to Africa. We uncover a previously unknown genetic lineage in the Levant similar to 200 BCE, which contributed increasing ancestry toward Asia. Donkey management involved inbreeding and the production of giant bloodlines at a time when mules were essential to the Roman economy and military. French National Research Agency (ANR) ANR-10-INBS-09 info:eu-repo/semantics/publishedVersion

Wild yak (Bos mutus) and domestic yak (Bos grunniens) are adapted to high altitude environment and have ecological, economic, and cultural significances on the Qinghai-Tibetan Plateau (QTP). Currently, the genetic and cellular bases underlying adaptations of yak to extreme conditions remains elusive. In the present study, we assembled two chromosome-level genomes, one each for wild yak and domestic yak, and screened structural variants (SVs) through the long-read data of yak and taurine cattle. The results revealed that 6733 genes contained high-FST SVs. 127 genes carrying special type of SVs were differentially expressed in lungs of the taurine cattle and yak. We then constructed the first single-cell gene expression atlas of yak and taurine cattle lung tissues and identified a yak-specific endothelial cell subtype. By integrating SVs and single-cell transcriptome data, we revealed that the endothelial cells expressed the highest proportion of marker genes carrying high-FST SVs in taurine cattle lungs. Furthermore, we identified pathways which were related to the medial thickness and formation of elastic fibers in yak lungs. These findings provide new insights into the high-altitude adaptation of yak and have important implications for understanding the physiological and pathological responses of large mammals and humans to hypoxia.

To develop a new classification of acromion based on the subacromial impingement theory and the Rockwood tilt view. And explore the application value of the new classification in the diagnosis and treatment of rotator cuff tear.The clinical data of 101 patients underwent shoulder arthroscopic surgery for impingement syndrome or rotator cuff tear from January to December 2017 were retrospectively analyzed. There were 34 males and 67 females, aged from 34 to 76 years with an average of (56.31±9.63) years old, course of disease from 2 to 12 months with average of 6 months. Preoperative radiographs of the routine anteroposterior view, Rockwood tilt view and the supraspinatus outlet view were obtained. Based on the subacromial impingement theory and Rockwood radiographs, the morphology of the acromion can be divided into three types:typeⅠ(flat type), typeⅡ(bump type), and type Ⅲ (impingement type). Two observers classified 101 shoulder Rockwood radiographs according to the new classification method and the supraspinatus Outlet radiographs according to the traditional acromial morphological classification method. Supraspinatus tendon injuries were classified into no tear, partial-thickness tear, and full-thickness tear according to the arthroscopic findings. Concordance test (Kappa value) between the inter-observer and intra-observer was carried out for the new classification method and the traditional classification method respectively. The rank sum test was used to compare the mean acromiohumeral distance(AHD) of the three acromion forms in the new acromion classification method. Spearman rank correlation test and Gamma method were used to analyze the correlation between the new acromion classification method and the degree of supraspinatus tendon tear.The inter-observer consistency analysis of the new classification system was significantly better than that of the traditional classification (0.827 vs 0.278), the intra-observer consistency analysis of the new classification system were also significantly better than that of the traditional classification (0.921 vs 0.448, 0.890 vs 0.539). There was no statistical significance in the AHD among three types of the new classification(Rockwood radiographs of the shoulder can well display the anterolateral osteophytes of the acromion. The new acromion classification method based on Rockwood radiographs has high reliability and good reproducibility, in which impingement type of acromion is closely related to supraspinatus tendon tear. Compared with the traditional classification and AHD, the new classification method has more diagnostic value than for rotator cuff injury.

Introduction Alcohol consumption has been steadily increasing in East Asia, however, there is comparatively little regional data of alcohol-related harms. This study examines the alcohol-related harms prevalence and risk factors in Hong Kong, a high population density city with limited alcohol regulation. Methods A cross-sectional telephone survey was conducted in 2019 on Chinese adults aged 18-74 (n = 3200). Respondents were asked about various past-year first-hand drinking harms (after one's own drinking), second-hand harms (harms from other people's drinking) and views of neighbourhood alcohol outlet regulation. Results Of drinkers, 21.1% reported first-hand alcohol harms, with physical/mental health harms (15.7%) most commonly reported. Younger-aged drinkers (adjusted odds ratios [AOR] 2.64, 95% confidence interval [CI] 1.63, 4.48) and heavy drinkers (AOR 2.34, 95% CI 1.55, 3.55) were more likely to report first-hand harms. Of the sample, 18.2% experienced past-year second-hand harms, with public harms (12.9%) most commonly reported. Young age (AOR 1.88, 95% CI 1.43, 2.49), higher education (AOR 1.44, 95% CI 1.13, 1.83), past-year binge drinking (AOR 4.29, 95% CI 3.04, 6.05) and communal living (AOR 2.04, 95% CI 1.13, 3.75) predicted greater likelihood of second-hand alcohol harms. Higher neighbourhood alcohol outlet density was not associated with any first-hand harms and only significantly predicted being inconvenienced by drinkers. Although victims of second-hand alcohol harms were more supportive of regulating outlet density, 93.3% of respondents were opposed to such policies. Discussion and conclusions Although high levels of alcohol-related harms were not reported by Hong Kong adults, regulations should target young drinkers and binge drinkers who are most likely to experience drinking-related harms.

MicroRNAs, as a group of post-transcriptional regulators, regulate multiple pathological processes including metastasis during tumor development. Here, we demonstrated the metastasis-suppressive function of microRNA (miR)-338-5p in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-338-5p had inhibitory effect on invasive ability of ESCC cells and extracellular matrix degradation, whereas silencing miR-338-5p had opposite effects. Mechanistically, miR-338-5p directly targeted the 3′ untranslated regions of hepatocellular growth factor receptor cMet (cMET) and epidermal growth factor receptor (EGFR). As a result, miR-338-5p inhibited the downstream signaling cascades of cMET and EGFR and repressed cMET- and EGFR-mediated ESCC cell invasion. Re-expression of cMET or EGFR in miR-338-5p overexpressing ESCC cells was sufficient to derepress ESCC cell invasion both in vitro and in vivo. We further showed that such manipulation downregulated the expression and secretion of matrix metalloproteinases 2 and 9, which resulted in impaired extracellular matrix degradation and cell invasion. Most importantly, systemic delivery of miR-338-5p mimic significantly inhibited metastasis of ESCC cells in nude mice. Taken together, our results uncovered a previously unknown mechanism through which miR-338-5p suppresses ESCC invasion and metastasis by regulating cMET/EGFR-matrix metalloproteinase 2/9 axis and highlighted the potential significance of miR-338-5p-based therapy in treating patients with metastatic ESCC.

Objective To examine the altitude differences in the optimal perfusate oxygenation (PpO2) in patients who underwent cardiac surgery. Methods We included children (aged 1 month to 18 years) with congenital heart diseases surgically repaired between 2012 and 2018. We included only patients who underwent cardiac surgery with arrested heart cardiopulmonary bypass. Primary outcome was severe systemic inflammatory response syndrome (SIRS). Logistic regression was used to evaluate the association between arterial PpO2 on continuous and categorical scales and severe SIRS by altitude. We established PpO2 thresholds that equated to a risk probability of roughly 0.185 or greater for developing severe SIRS in each group of altitude. Results Among 3918 patients from low altitudes and 2384 from high altitudes, high-altitude patients were older (median, 42.3 [interquartile range 22.8-75.8] vs 37.1 [17.7-69.1] months, P Conclusions This study suggests altitude differences in the association of arterial PpO2 with inflammatory response following pediatric cardiac surgery.

This study aimed to develop a mapping function that links the acromegaly quality of life (AcroQoL) questionnaire to EQ-5D-5L to obtain a preference-based utility value to inform economic evaluation. A nationwide cross-sectional questionnaire survey among patients with acromegaly was conducted online in China during 17 December 2019 to 6 January 2020. The study sample was randomly divided into a training set and a validation set. Ordinary least squares (OLS), Tobit, beta-based mixture, and adjusted limited dependent variable mixture models were tested for development of the function in the training set. Total and subscale scores and individual items of AcroQoL were included as predictors in the models along with their squared terms and demographic and clinical characteristics, and selected by backward stepwise selection. The root mean square error, mean absolute error, Akaike’s information criterion, Bayesian information criterion and adjusted R-square were used to assess goodness of fit and predictive ability of the models. There were 424 adult patients with acromegaly eligible for this analysis. Average EQ-5D-5L index score and AcroQoL score for them was 0.82 (SD = 0.15) and 44.3 (SD = 22.9), respectively. A total of 60 candidate models were tested. Considering model simplicity and predictive ability in both training and validation set, the best model was the OLS model using scores of physical dimension and its square term as predictors. A validated mapping function was developed in this study for estimating EQ-5D scores using AcroQoL outcomes. Its external validity can be further tested in other population with Acromegaly.

This study aimed to explore the quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients using model-based meta-analysis (MBMA).Literatures were retrieved from the public database and data from these trials were extracted. The quantitative efficacy of L-carnitine on fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) in type 2 diabetes mellitus patients were evaluated by maximal effect (EIn the model of FPG, EIt was the first time to provide valuable quantitative information for efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients.

Background Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated. Methods MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. Results MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST. Conclusions Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC., Low expression of miR‐125b‐2‐3p in CRC was linked to lower chemotherapeutic sensitivity and poor survival. The lncRNA XIST promoted CRC invasion and migration by functioning as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. Our findings suggest that the lncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC, which may shed light on their targeted applications.

The aim of this study was to evaluate the psychometric properties of the EQ-5D-5L and SF-6D, and to compare their performance among patients living with haemophilia in China. A total of 875 Chinese patients completed the EQ-5D-5L, SF-6D, and Haem-A-QoL questionnaires. Construct validity of the EQ-5D-5L and SF-6D dimensions and indices was assessed by testing hypotheses relating these measures to Haem-A-QoL and clinical measures. The Spearman correlation coefficient was used to assess convergent validity, and one-way analysis of variance (F statistic) was used to assess the known-groups validity (discriminatory power). The agreement between EQ-5D-5L and SF-6D indices was assessed using the intraclass correlation coefficient (ICC) and the Bland–Altman plot. Both the EQ-5D-5L and SF-6D indices showed acceptable ceiling and floor effects. As hypothesised, both EQ-5D-5L and SF-6D were significantly correlated with Haem-A-QoL (both dimensions and overall score). EQ-5D-5L and SF-6D indices as well as EQ-VAS differentiated patients are known to differ in severity of haemophilia, bleeding status, disabling levels, and comorbidity. The F statistics in the known-groups comparisons suggested that the EQ-5D-5L was slightly more discriminative than the SF-6D. ICC (0.41) and Bland–Altman plot confirmed that the agreement between the EQ-5D-5L and SF-6D indices was poor. Both EQ-5D-5L and SF-6D showed satisfactory construct validity in the measurement of the HRQoL among patients with haemophilia. However, the two instruments may not be used interchangeably in this patient population due to their poor agreement and differing discriminatory power.

BACKGROUND The present study aimed to explore the effectiveness of electro-acupuncture (EA) in combination with a local anesthetic used in Western medicine in preventing the side effects of gastroscopy. METHODS A sample group of 150 patients were divided into three groups based on treatment methods: an EA group, a dyclonine hydrochloride mucilage group, and a combined treatment group. In the EA group, EA stimulation was given at the Hegu, Neiguan, and Zusanli acupoints; in the dyclonine hydrochloride mucilage group, patients took 10 mL of dyclonine hydrochloride mucilage orally; in the combined treatment group, prevention of side effects was attempted by administration of both acupuncture and oral local anesthetic. The incidences of nausea, emesis, salivation, cough, restlessness, and breath holding during gastroscopy were observed and recorded for the three groups. Mean arterial pressure, heart rate, and oxygen saturation were recorded before the examination, and changes in these measures were recorded as the gastroscope passed through the pylorus and after the examination. The visual analogue scale (VAS) values of nausea and emesis, the rate of successful first-pass intubation, and the time of gastroscopy were also recorded. Statistical analysis was performed using R-3.5.3 software. RESULTS Incidences of side effects (e.g., nausea, emesis, salivation, restlessness, and breath holding) during the examination were lower in the combined treatment group than in the EA group and the dyclonine hydrochloride mucilage group (P

T helper (Th) 2 cell-medicated immune response participates in various immune diseases, including systemic lupus erythematosus (SLE). Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be associated with T helper 2 (Th2) cell activation. Here, we demonstrated the molecular mechanism of NEAT1 in regulating Th2 cell activation. We found that NEAT1 was located in nucleus. NEAT1 overexpression promoted the levels of Th2-related cytokines IL-4, IL-5 and IL-13 in CD4+ T cells. Moreover, NEAT1 up-regulation reduced Th1-related cytokine INF-γ production and enhanced the levels of Th17-related cytokines IL-17 in CD4+ T cells. STAT6 deficiency reduced the levels of IL-4, IL-5, IL-13 and IL-17 enhanced the levels of INF-γ in CD4+ T cells, which was rescued by NEAT1 overexpression. Moreover, NEAT1 promoted STAT6 protein expression, whereas NEAT1 had no effect on the expression of STAT6 mRNA. Furthermore, NEAT1 interacted with STAT6, inhibited the ubiquitination of STAT6 in CD4+ T cells. In conclusion, our work has confirmed that NEAT1 promotes STAT6 expression by inhibiting STAT6 ubiquitination, thereby promoting Th2 cell activation. Thus, our work may highlight novel insights into the molecular mechanism of NEAT1 in regulating Th2 cell activation.

Thyroid cancer (TC) is one of the most common malignant tumors, with high morbidity and mortality rates worldwide. The incidence of TC, especially that of papillary thyroid carcinoma (PTC); has increased rapidly in recent decades. Autoimmune thyroid disease (AITD) is closely related to TC and has an estimated prevalence of 5%. Thus, it is becoming increasingly important to identify potential diagnostic biomarkers and therapeutic targets for TC and AITD. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently bonded circular structures that lack 5'-3' polarity and polyadenylated tails. Several circRNAs play crucial roles in the development of various diseases, including TC and AITD, and could be important new biomarkers and/or targets for the diagnosis and therapy of such disorders. Although there are four subtypes of TC, research on circRNA has largely focused on its connection to PTC. Therefore, this review mainly summarizes the relationships between circRNAs and PTC and AITD, including the molecular mechanisms underlying these relationships. In particular, the functions of "miRNA sponges" and their interactions with proteins and RNA are discussed. The possible targeting of circRNAs for the prevention, diagnosis, and treatment of TC and AITD is also described. CircRNAs could be potential biomarkers of TC and AITD, although validation will be required before they can be implemented in clinical practice.

Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC). Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival. Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival. Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.

Background To compare the efficacy of three different fixation methods of fibula combined with external fixation of tibia for the treatment of extra-articular open fractures of distal tibia and fibula. Methods From January 2017 to July 2019, 91 cases of open fractures of distal tibia and fibula were treated with external fixator, and the fibula was fixed with non-fixation (group A, n = 35), plate-screw (group B, n = 30) and Kirschner wire (group C, n = 26). The operation time, intraoperative blood loss, surgical and implants costs, fracture healing time, postoperative complications, and American Orthopaedic Foot and Ankle surgery (AOFAS) scores were compared among the groups. Results Four patients were lost to follow-up, and 87 patients were followed up for 5–35 months (average, 14.2 months). The operation time of group C (114.92 ± 36.09 min) was shorter than that of group A (142.27 ± 47.05 min) and group B (184.00 ± 48.56 min) (P P > 0.05). The surgical and implants costs in group C (5.24 ± 1.21, thousand dollars) is lower than that in group A (6.48 ± 1.11, thousand dollars) and group B (9.37 ± 2.16, thousand dollars) (P P P P > 0.05). The excellent or good rate of ankle function was 69.70% in group A, 72.41% in group B and 84.00% in group C, with no statistical difference among the three groups (P > 0.05). Conclusion Compared with simple external fixator fixation and external fixator combined with plate-screw osteosynthesis, external fixator combined with K-wire intramedullary fixation shortens the operative time and fracture healing time, reduced costs and complications of fracture healing, while the blood loss, infection complications and ankle function recovery showed no difference with the other two groups. External fixator combined with plate-screw osteosynthesis had no advantage in treating extra-articular open fractures of distal tibia and fibula when compared with simple external fixation.

The agricultural non-point source pollution (ANPSP) load in Guangdong province is very large and has a serious impact on the regional ecological environment. Inventory analysis was used to assess and analyze the temporal and spatial variation characteristics of the ANPSP load of Guangdong province during 1999-2019, and the sources of ANPSP were discussed, as well as the relationship between them. The results showed that, during the past 20 years, the total ANPSP pollution loads of Guangdong province decreased by 6.08%, and the pollution loads of chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) increased by -11.88%, 4.99%, and 26.17%, respectively. The input intensity of chemical fertilizers and pesticides increased by 112.19% and 60.38%, respectively. The Pearl River Delta had the highest ANPSP loads in Guangdong province, followed by those in northern, western, and eastern Guangdong. Livestock and poultry breeding were the main sources of COD, the total percent fertilizers and livestock and poultry breeding were the main sources of TN, and livestock and poultry breeding and aquaculture were the main sources of TP. In addition, the contribution of pollutants discharged from aquaculture showed an obvious increasing trend. There were certain differences in the pollution sources in different regions. In western Guangdong, northern Guangdong, and eastern Guangdong, livestock and poultry breeding were the main sources of COD and TP, and fertilizer was the main source of TN; by contrast in the Pearl River Delta, aquaculture had become the main source of TN and TP pollution loads. The correlation results showed that the decline in the total ANPSP in Guangdong province was mainly due to the increase in high urbanization rate and the decrease in the proportion of rural population. In general, there were stage changes in the time and differences in spatial characteristics and sources of ANPSP in Guangdong province. A combination of comprehensive treatment and targeted pollution treatment should be adopted, and fertilizer reduction measures and pollution treatment in the aquaculture should be strengthened in an all-around way, focusing on strengthening the treatment of pollution from aquaculture in the Pearl River Delta region and the treatment of rural life pollution in northern Guangdong.

Immunomagnetic nanoparticles (IMNs) have been widely developed as a detection tool to isolate rare circulating tumor cells (CTCs) from whole blood as a potential method for early cancer diagnosis, metastasis examination, and treatment guidance. However, a spontaneous interaction between nanoparticles and proteins results in the formation of a protein corona that reduces the performance of IMNs when they enter body fluids. To address this issue, the protein corona was precoated onto magnetic nanoparticles (C-MNs), and then their surfaces were conjugated with an immuno-antibody. The adsorption of proteins on C-MNs was decreased 6-fold and non-specific cell binding was reduced 5-fold, compared with magnetic nanoparticles (MNs). Furthermore, the immuno-antibody functionalized C-MNs (IC-MNs) maintained highly specific CTC capture performance when exposed to blood plasma. By using artificial spiked blood samples, IC-MNs exhibited 90.2% CTC isolation efficiency, compared with 60.3% by using IMNs. IC-MNs also successfully captured CTCs with high purity in 24 out of 26 female breast cancer patient blood samples. This work demonstrated that a novel preformed protein corona strategy can provide a useful clinically applicable diagnostic tool.

Background Colorectal cancer is one of the most common cancers in the world. Several studies suggest using the Asia-Pacific colorectal screening (APCS) score and its modified versions to select high-risk populations for early colonoscopy, but external validation remains rare, and which score should be selected for CRC screening in China is unclear. Validation of multiple scores in the same population might help to choose the best performing score. Methods We conducted a cross-sectional study under the framework of Cancer Screening Program in Urban China, data from asymptomatic colorectal cancer screening in Xuzhou was used to validate the APCS score, the colorectal neoplasia predict (CNP) score, the Korean colorectal screening (KCS) score, the Modified APCS score and the 8-point risk score in predicting colorectal advanced neoplasia (CAN). Results 1804 subjects were included in the analysis and 112 CAN (6.21%) was detected. In each score, the detection rate of CAN was higher in the high-risk group than in the non-high-risk group (P RR (95%C.I.) ranged 2.20 (1.50–3.22) [8-point risk] to 4.00 (2.41–6.65) [Modified APCS]. The c-statistics (95%C.I.) of the scoring systems ranged from 0.58 (0.53–0.62) [8-point risk] to 0.65 (0.61–0.69) [KCS]. The sensitivity (95%C.I.) of these systems ranged from 31.25 (22.83–40.70) [8-point risk] to 84.82 (76.81–90.90) [Modified APCS], while the specificity (95%C.I.) ranged from 43.50 (41.12–45.90) [Modified APCS] to 83.81 (81.96–85.53) [8-point risk]. Using the APCS scoring system as a comparator, the net reclassification improvement (NRI) of each modified version ranged from − 10.34% (95%C.I.: − 22.63 to 1.95%) [8-point risk] to 4.79% (95%C.I.: − 1.50% to 11.08) [KCS]. The colonoscopy resource load (95%C.I.) ranged from 9 [1–3] [8-point risk] to 11 [3–5] [APCS and Modified APCS]. Conclusions The APCS score and its modified versions have certain ability to predict the risk of advanced neoplasia and reduce the resource load. The modified APCS score and the KCS score seemed the preferable systems to classify high risk subjects based on its high RR, sensitivity and predictive ability in the selected population. Future research could focus on adding risk factors or combining with laboratory test results to improve the predictive power of the scoring system.

To investigate the effect of internal external fixator assisted O-arm navigation imaging in the treatment of unstable pelvic fractures.From May 2019 to November 2019, 15 patients with unstable pelvic fractures were treated by intraoperative O-arm navigation imaging using INFIX technology. There were 6 males and 9 females. The age ranged from 24 to 66 years old. The course of disease ranged from 2 to 14 days. According to Tile classification, there were 1 case of B1 type, 8 cases of B2 type, 3 cases of C1 type, and 3 cases of C2 type. According to Young-Burgess classification, there were 8 cases of LC, 1 case of APC, 4 cases of VS, 2 cases of CM. Preoperative routine pelvic anteroposterior film, entrance position, exit position and pelvic CT three-dimensional reconstruction were performed. Intraoperative O-arm navigation system three-dimensional reconstruction and triplane scanning imaging were used to evaluate the effect of intraoperative reduction. The anterior pelvic ring was fixed with internal external fixator, and the posterior ring was fixed with sacroiliac screw, plate screw or lumbar iliac screw. The operation time, intraoperative bleeding and nail placement were observed and recorded. The quality of fracture reduction was evaluated by Matta standard, and the postoperative function was evaluated by Majeed function score.Wound healing was good in all patients without vascular, nerve and local irritation complications. All the 15 patients were followed up for 10 to 16 months. The fracture reduction was evaluated according to the Matta scoring standard, 9 cases were excellent results, 5 cases were good, and 1 case was medium. The Majeed functional score was 0 to 95 points.The built-in external fixator assisted O-arm navigation imaging system in the treatment of unstable pelvic fractures. The reduction effect is evaluated in advance, the operation time is shortened, and the accuracy of internal fixation is improved. The operation is simple, safe and less bleeding. The operation is in line with the principles of minimally invasive medical treatment and precision medical treatment in orthopedics, which is conducive to the recovery of patients' postoperative function and rapid recovery.

Background Breast cancer (BCa) is the leading cause of cancer deaths among women. Reliable biomarkers for early diagnosis and metastasis prediction are essential to improve the prognosis of BCa. This study aimed to evaluate serum periostin (POSTN) as a novel biomarker complementing CA153 (carbohydrate antigen 153) and CEA (carcinoembryonic antigen) for BCa diagnosis and metastasis prediction. Methods To assess the potential of soluble POSTN as a circulating biomarker, 242 participants, including 173 patients with different stages of BCa and 69 healthy individuals, were enrolled in this study. Soluble POSTN, together with CA153 and CEA, were determined in serum by enzyme linked immunosorbent assay (ELISA) or electrochemiluminescence immunoassays. Results Serum POSTN levels in locoregional BCa patients were significantly higher than that in healthy controls. Receiver operating curve (ROC) analysis revealed that, to distinguish health controls from locoregional BCa, POSTN was observed with the highest AUC (area under curve) (AUCPOSTN = 0.72 [0.65 – 0.79], AUCCA153 = 0.57 [0.49 – 0.64], AUCCEA = 0.62 [0.55 – 0.69]), and both CA153 and CEA were observed with significantly improved AUCs by combination with POSTN (AUCPOSTN + CA153 = 0.74 [0.67 – 0.80], P POSTN + CEA = 0.77 [0.70 – 0.82], P POSTN = 0.78 [0.71 – 0.84], AUCCA153 = 0.82 [0.76 – 0.88]). Kaplan–Meier analysis indicated that elevated serum POSTN was associated with poor overall survival and progression-free survival. Conclusions This study suggested that soluble POSTN is a promising potential biomarker for diagnosis and metastasis prediction of BCa.

BackgroundTo counter the harms caused by alcohol use, the World Health Organization (WHO) outlined a series of evidence-based recommendations, including the highly cost-effective “Best Buys” recommendations. While many Western countries have been actively introducing alcohol harms reduction strategies, it is unclear whether these cost-effective policies would be publicly acceptable in Asian regions with traditionally low alcohol consumption. This study examines the public acceptability of WHO-recommended alcohol harms reduction strategies in an Asian city with few extant alcohol regulations.MethodsA cross-sectional telephone survey of Hong Kong Chinese residents aged 18–74 (n = 4,000) was conducted from January to August 2018. Respondents were asked about their perceptions of various WHO-recommended strategies and consequences of their implementation. After reducing the strategies into several policy categories by principal component analysis, multivariable linear regression was performed to identify factors associated with endorsement of the various policies.ResultsAmong the “Best Buys”, introduction of moderate beer/wine taxes (68.7%) and shortened alcohol retail hours (51.9%) were the most supported while bans on event sponsorships (19.5%) and public drinking events (17.7%) were the least popular. Strategies targeting young drinkers were particularly highly supported. Males, younger adults, Non-abstainers, and those who believed in drinking's social benefits were less likely to endorse stringent control measures (p < 0.05). Adults with higher household income were less supportive, partially due to concerns about infringements on local economy, lifestyles, and economic freedom. Women and older people were generally more supportive, partially because they perceived these policies would lower alcohol-related harms.ConclusionIn order to reduce barriers to implementing WHO-recommended strategies in the region, it is imperative to increase awareness of alcohol-related harms and to strengthen beliefs in the effectiveness of these countermeasures, especially among men, young adults, and drinkers.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1–G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1–G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7–G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9–G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Background De Winter electrocardiograph (ECG) pattern is an atypical presentation of acute myocardial infarction (AMI) due to severe stenosis of the left anterior descending (LAD). Complications of acute aortic dissection (AD) in the setting of acute myocardial infarction (AMI) with de Winter sign are relatively rare and physicians may easily miss the diagnosis of AD. We report a case of patient with acute chest pain and de Winter ECG pattern due to AD involving the left main coronary artery (LM), LAD and left circumflex artery (LCX). Case presentation A 57-year-old male patient was initially diagnosed with AMI and then the diagnosis of acute AD was supported by transthoracic echocardiograph (TTE). After two stents were implanted respectively into the proximal LM-LAD and LM-LCX, he recovered from cardiogenic shock. Two months later, the patient underwent the surgery of ascending aorta replacement. After the surgery, there was no obvious chest discomfort during follow-up. Conclusions When an ECG shows a “de Winter pattern”, we should also consider the possibility of AD which result in LAD occlusion. TTE is a useful tool in screening for AD. Further research is needed to prove that percutaneous coronary intervention (PCI) may be a useful treatment strategy in the case of AD leading to severe LAD occlusion and unstable hemodynamics when there’s no condition to perform aortic replacement surgery immediately.