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Abstract The aim of our study was to develop robust diagnostic and prognostic models for lung adenocarcinoma (LUAD) using machine learning (ML) techniques, focusing on early immune infiltration. Feature selection was performed on The Cancer Genome Atlas (TCGA) data using least absolute shrinkage and selection Operator (LASSO), random forest (RF), and support vector machine (SVM) algorithms. Six ML algorithms were employed to construct the diagnostic models, which were evaluated through receiver operating characteristic (ROC) curves, precision-recall curves (PRC), and classification error (CE), and validated on the GSE7670 dataset. Additionally, a lasso cox prognostic model was built on the TCGA-LUAD dataset and externally validated using independent Gene Expression Omnibus datasets (GSE30219, GSE31210, GSE50081, and GSE37745). Single-sample gene set enrichment analysis (ssGSEA) was performed to assess immune cell infiltration in stage I LUAD samples, revealing significant differences in immune cell types. These findings demonstrate a positive correlation between immune infiltration in stage I LUAD and Th2 cells, Tcm cells, and T helper cells, while a negative correlation was observed with Macrophages, Eosinophils, and Tem cells. These insights provide novel perspectives for clinical diagnosis and treatment of LUAD.

Abstract Pressure drifting is a troublesome error in invasive coronary function tests. This study aimed to evaluate the relationship between prolonged and short-time pressure equalizations in pressure drifting. Pressure drifting was defined as the pressure gradient between the mean pressure of the distal wire sensor (Pd) and aortic pressure (Pa) when the wire was withdrawn to the tip of the guiding catheter. Significant drifts 1 and 2 were defined as the absolute values of pressure gradients > 2 and > 3 mmHg, respectively. A logistic regression model was used to evaluate the associations between prolonged pressure equalization and each pressure drifting. The prolonged pressure equalization strategy was associated with a lower incidence of drift 1 than the short-time pressure equalization strategy (6.84% vs. 16.92%, p

Abstract Numerous studies have indicated a connection between psychiatric symptoms, specifically anxiety and depression, and gastroesophageal reflux. However, the precise nature of the link between the severity of gastroesophageal reflux disease and the severity of anxiety and depression remains uncertain. Here, we gathered 24-h pH monitoring data and baseline patient information from a cohort of 518 individuals. Additionally, we evaluated their psychological well-being using the Hospital Anxiety and Depression Scale. The relationship between baseline characteristics and varying degrees of anxiety, depression, and gastroesophageal reflux disease (GERD) was assessed using R software version 4.1.3 and logistic regression models. The findings indicate a statistically significant variation in anxiety levels based on gender, as well as a significant disparity in depression groups when considering age and literacy levels. Kruskal–Wallis test analysis revealed a significant positive correlation between the severity of anxiety and depression and the 24-h pH monitoring results in our patient cohort. As the anxiety and depression levels increased, the rank mean for each examination result also increased. Logistic regression modeling analysis showed that a higher anxiety level was associated with a higher level of GERD. In the presence of mild anxiety, there is a statistically significant association with a higher incidence of GERD with an odds ratio (OR) of 2.64 (95% CI 1.50, 4.64). Similarly, the moderately severe anxiety group also exhibits a causal relationship with an increased GERD incidence, with an OR of 6.84 (95% CI 3.92, 12.17). Additionally, moderate to severe depression is associated with a higher incidence of GERD, with an OR of 2.32 (95% CI 1.23, 4.37). The prevalence of GERD was greater among males compared to females (OR 2.29, 95% CI 1.51–3.49). Additionally, an elevated body mass index (BMI) demonstrated a positive correlation with the susceptibility to GERD (OR 1.07, 95% CI 1.01–1.14). Increasing age may promote the occurrence of GERD in patients. These findings may help to provide a better basis for psychological or pharmacological interventions for GERD patients with psychosomatic symptoms in the future, and provide a reference basis for clinical treatment of the disease.

Abstract Currently, the classification of bone mineral density (BMD) in many research studies remains rather broad, often neglecting localized changes in BMD. This study aims to explore the correlation between peri-implant BMD and primary implant stability using a new artificial intelligence (AI)-based BMD grading system. 49 patients who received dental implant treatment at the Affiliated Hospital of Stomatology of Fujian Medical University were included. Recorded the implant stability quotient (ISQ) after implantation and the insertion torque value (ITV). A new AI-based BMD grading system was used to obtain the distribution of BMD in implant site, and the bone mineral density coefficients (BMDC) of the coronal, middle, apical, and total of the 1 mm site outside the implant were calculated by model overlap and image overlap technology. Our objective was to investigate the relationship between primary implant stability and BMDC values obtained from the new AI-based BMD grading system. There was a significant positive correlation between BMDC and ISQ value in the coronal, middle, and total of the implant (P 0.05). Furthermore, BMDC was notably higher at implant sites with greater ITV (P

Abstract. Background:. To perform anatomical anterior cruciate ligament reconstruction (ACLR), tunnels should be placed relatively higher in the femoral anterior cruciate ligament (ACL) footprint based on the findings of direct and indirect femoral insertion. But the clinical results of higher femoral tunnels (HFT) in double-bundle ACLR (DB-ACLR) remain unclear. The purpose was to investigate the clinical results of HFT and lower femoral tunnels (LFT) in DB-ACLR. Methods:. From September 2014 to February 2016, 83 patients who underwent DB-ACLR and met the inclusion and exclusion criteria were divided into HFT-ACLR (group 1, n = 37) and LFT-ACLR (group 2, n = 46) according to the position of femoral tunnels. Preoperatively and at the final follow-up, clinical scores were evaluated with International Knee Documentation Committee (IKDC), Tegner activity, and Lysholm score. The stability of the knee was evaluated with KT-2000, Lachman test, and pivot-shift test. Cartilage degeneration grades of the International Cartilage Repair Society (ICRS) were evaluated on magnetic resonance imaging (MRI). Graft tension, continuity, and synovialization were evaluated by second-look arthroscopy. Return-to-sports was assessed at the final follow-up. Results:. Significantly better improvement were found for KT-2000, Lachman test, and pivot-shift test postoperatively in group 1 (P >0.05). Posterolateral bundles (PL) showed significantly better results in second-look arthroscopy regarding graft tension, continuity, and synovialization (P 0.05). No statistically significant differences were found in IKDC subjective score, Tegner activity, and Lysholm score between the two groups. Higher return-to-sports rate was found in group 1 with 86.8% (32/37) vs. 65.2% (30/46) in group 2 (P = 0.027). Conclusion:. The HFT-ACLR group showed better stability results, better PL, and higher return-to-sports rate compared to the LFT-ACLR group.

Abstract Background Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men worldwide, and its incidence has risen substantially in recent years. Therefore, there is an urgent need to identify novel biomarkers and precise therapeutic targets for managing PCa progression and recurrence. Methods We investigated the clinical significance of NCAPG2 in PCa by exploring public datasets and our tissue microarray. Receiver operating characteristic (ROC) curve and survival analyses were performed to evaluate the correlation between NCAPG2 and PCa progression. Cell proliferation, wound healing, transwell, flow cytometry, cell cycle, tumor sphere formation, immunofluorescence (IF), co-immunoprecipitation (co-IP), and chromatin immunoprecipitation (ChIP) assays were conducted to further elucidate the molecular mechanism of NCAPG2 in PCa. Subcutaneous and orthotopic xenograft models were applied to investigate the effects of NCAPG2 on PCa proliferation in vivo. Tandem mass tag (TMT) quantitative proteomics was utilized to detect proteomic changes under NCAPG2 overexpression. Results NCAPG2 was significantly upregulated in PCa, and its overexpression was associated with PCa progression and unfavorable prognosis. Knockdown of NCAPG2 inhibited the malignant behavior of PCa cells, whereas its overexpression promoted PCa aggressiveness. NCAPG2 depletion attenuated the development and growth of PCa in vivo. TMT quantitative proteomics analyses indicated that c-MYC activity was strongly correlated with NCAPG2 expression. The malignancy-promoting effect of NCAPG2 in PCa was mediated via c-MYC. NCAPG2 could directly bind to STAT3 and induce STAT3 occupancy on the MYC promoter, thus to transcriptionally activate c-MYC expression. Finally, we identified that NCAPG2 was positively correlated with cancer stem cell (CSC) markers and enhanced self-renewal capacity of PCa cells. Conclusions NCAPG2 is highly expressed in PCa, and its level is significantly associated with PCa prognosis. NCAPG2 promotes PCa malignancy and drives cancer stemness via the STAT3/c-MYC signaling axis, highlighting its potential as a therapeutic target for PCa.

Abstract Gastrointestinal symptoms are more prevalent in children with autism spectrum disorder (ASD) than in typically developing (TD) children. Constipation is a significant gastrointestinal comorbidity of ASD, but the associations among constipated autism spectrum disorder (C-ASD), microbiota and short-chain fatty acids (SCFAs) are still debated. We enrolled 80 children, divided into the C-ASD group (n = 40) and the TD group (n = 40). In this study, an integrated 16S rRNA gene sequencing and gas chromatography–mass spectrometry-based metabolomics approach was applied to explore the association of the gut microbiota and SCFAs in C-ASD children in China. The community diversity estimated by the Observe, Chao1, and ACE indices was significantly lower in the C-ASD group than in the TD group. We observed that Ruminococcaceae_UCG_002, Erysipelotrichaceae_UCG_003, Phascolarctobacterium, Megamonas, Ruminiclostridium_5, Parabacteroides, Prevotella_2, Fusobacterium, and Prevotella_9 were enriched in the C-ASD group, and Anaerostipes, Lactobacillus, Ruminococcus_gnavus_group, Lachnospiraceae_NK4A136_group, Ralstonia, Eubacterium_eligens_group, and Ruminococcus_1 were enriched in the TD group. The propionate levels, which were higher in the C-ASD group, were negatively correlated with the abundance of Lactobacillus taxa, but were positively correlated with the severity of ASD symptoms. The random forest model, based on the 16 representative discriminant genera, achieved a high accuracy (AUC = 0.924). In conclusion, we found that C-ASD is related to altered gut microbiota and SCFAs, especially decreased abundance of Lactobacillus and excessive propionate in faeces, which provide new clues to understand C-ASD and biomarkers for the diagnosis and potential strategies for treatment of the disorder. This study was registered in the Chinese Clinical Trial Registry ( www.chictr.org.cn ; trial registration number ChiCTR2100052106; date of registration: October 17, 2021).

Abstract Background Intestinal lymphangiectasia (IL) is a rare protein-losing enteropathy caused by disorders of the intestinal lymphatics. There are only a few case reports and case series concerning the VCE (video capsule endoscopy) findings of IL. This work aimed to evaluate the VCE characteristics of small intestinal mucosal abnormalities in patients with IL, and to investigate the relationship between clinical and VCE characteristics. Methods Consecutive patients with IL who underwent VCE were enrolled in this retrospective study. The cases were classified into the white villi group and non-white villi group according to mucosal abnormalities detected by VCE. Clinical and endoscopic characteristics were investigated and analyzed. Results A total of 98 patients with IL with a median onset age of 26.3 ± 19.2 years were included. VCE revealed the following small intestinal lesions: (i) white villi type (57/98, 58.2%), i.e.: white-tipped or granular villi, white nodular villi or plaques; (ii) non-white villi type (41/98, 41.8%), i.e.: diffused low and round villi; (iii) complications (46/98, 46.9%), i.e.: bleeding, ulcers, protruding or vesicular-shaped lesions, stenosis and lymphatic leakage. A total of 58.2% (57) and 41.8% (41) of the cases were classified into the white villi and non-white villi groups respectively. The percentage of chylothorax in the white villi group was significantly lower than that in the non-white villi group (12/57 vs. 19/41, p = 0.008). In VCE, there were no significant differences in the involved segments and total detected rate of complications between the white villi and non-white villi groups (p > 0.05), while the detected rate of lymphatic leakage in the white villi group was significantly higher than that in the non-white villi group (31.6% vs. 12.2%, p = 0.026). Conclusions Our study evaluated the entire small intestinal mucosal abnormalities of IL by VCE, especially endoscopic complications. IL has specific VCE abnormalities in addition to classical endoscopic findings.

Abstract To explore the efficacy and safety of fecal microbiota transplantation (FMT) as a treatment approach for ulcerative colitis (UC), a comprehensive systematic review and meta-analysis of randomized controlled trials was conducted. To collect and evaluate randomized controlled trials of high quality on FMT for UC, we searched a number of databases, including PubMed, Web of Science, Cochrane, Embase, and Medline, for studies published between the establishment of the databases and March 2023. We conducted a meta-analysis of the studies using Review Manager software (version 5.4.1) to determine the differences in rates of remission and adverse reactions between the FMT group and the control group, utilizing the risk ratio (RR) and 95% confidence interval (CI) to combine our findings. A total of 13 randomized controlled trials (RCTs) on the efficacy of FMT in patients with UC were included in the study, in which 580 patients participated, including 293 patients treated with FMT and 287 control subjects. Meta-analysis revealed that clinical remission was significantly better in the FMT group than in the control group [RR = 1.73; 95% CI = (1.41, 2.12); P

Abstract We assessed the effectiveness of light-guided-tip intense pulsed light (IPL) with meibomian gland expression (MGX) in chalazion treatment. Ninety-five eyes with chalazion received a light-guided-tip IPL-MGX treatment (IPL-MGX group), and another 95 eyes with chalazion received incision with curettage treatment (Control group). Prior to IPL or incision, as well as 1 month after the final treatment, data were gathered pertaining to the lesion location and size, hyperemia, lesions regression or recurrence, and a comprehensive ophthalmic examination. The total size of the chalazia in the IPL-MGX group was significantly reduced after the final treatment, with an average resolution rate of 70.5%, which is comparable to excision surgery. A significant decrease in chalazion recurrence rate was apparent after treatment in the IPL-MGX group compared with control. Moreover, the IPL-MGX demonstrated significant advancements throughout noninvasive tear film breakup time (NIBUT) as well as meibum grade in comparison to baseline and those in the the Control group. The use of IPL-MGX was found to be an efficient therapy for reducing the size and recurring frequency of chalazia, as well as for improving the meibomian gland function. It may be considered as a first-line treatment for cases of primary or recurrent chalazia with inflammation.

Abstract Background Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. Methods Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. Results Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45–0.59), and decreased HOMA-IR (β = − 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06–1.15), and decreased HOMA-B (β = − 0.04, SE = 0.01, P = 4.52 × 10–5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. Conclusions This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

BackgroundRapid proliferation and outgrowth of tumor cells frequently result in localized hypoxia, which has been implicated in the progression of lung cancer. The present study aimed to identify key long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in hypoxia-induced A549 lung cancer cells, and to investigate their potential underlying mechanisms of action.MethodsHigh-throughput sequencing was utilized to obtain the expression profiles of lncRNA and mRNA in both hypoxia-induced and normoxia A549 lung cancer cells. Subsequently, a bioinformatics analysis was conducted on the differentially expressed molecules, encompassing functional enrichment analysis, protein-protein interaction (PPI) network analysis, and competitive endogenous RNA (ceRNA) analysis. Finally, the alterations in the expression of key lncRNAs and mRNAs were validated using real-time quantitative PCR (qPCR).ResultsIn the study, 1155 mRNAs and 215 lncRNAs were identified as differentially expressed between the hypoxia group and the normoxia group. Functional enrichment analysis revealed that the differentially expressed mRNAs were significantly enriched in various pathways, including the p53 signaling pathway, DNA replication, and the cell cycle. Additionally, key lncRNA-miRNA-mRNA relationships, such as RP11-58O9.2-hsa-miR-6749-3p-XRCC2 and SNAP25-AS1-hsa-miR-6749-3p-TENM4, were identified. Notably, the qPCR assay demonstrated that the expression of SNAP25-AS1, RP11-58O9.2, TENM4, and XRCC2 was downregulated in the hypoxia group compared to the normoxia group. Conversely, the expression of LINC01164, VLDLR-AS1, RP11-14I17.2, and CDKN1A was upregulated.ConclusionOur findings suggest a potential involvement of SNAP25-AS1, RP11-58O9.2, TENM4, XRCC2, LINC01164, VLDLR-AS1, RP11-14I17.2, and CDKN1A in the development of hypoxia-induced lung cancer. These key lncRNAs and mRNAs exert their functions through diverse mechanisms, including the competitive endogenous RNA (ceRNA) pathway.

BackgroundThe state of Sarawak on the island of Borneo in East Malaysia, in working towards developing and strengthening cancer services through a holistic patient-centred approach, must focus on the comprehensive needs of cancer patients by taking into account the psycho-social, cultural and spiritual aspects of Sarawak's multi-ethnic, multi-cultural population.MethodsA 42-item survey questionnaire was developed and validated with a total of 443 patients. The perceived importance of information provided and level of patient satisfaction were assessed with a 5-point Likert scale in 10 domains (Diagnosis, Surgery, Radiotherapy, Systemic therapy, Clinical trials, Pain management, Treatment monitoring, Psychosocial support, Sexual care and fertility issues, and Financial support). A Spearman's rank correlation test was applied to determine the correlation between response in both item and domain categories for perceived importance and satisfaction.ResultsOverall, patients were more satisfied with information related to cancer diagnosis, treatment and surgery but less satisfied with information pertaining to sexual aspects of care and family planning, psycho-social support and financial support. The majority of patients were satisfied with the level of treatment-related information received but preferred the information to be delivered in more easily comprehendible formats. Sexual aspects of care and family planning, psychosocial support and treatment monitoring post-discharge were perceived as important but seldom addressed by health care professionals due to lack of professional counsellors, social workers and clinical nurse specialists. Many patients face financial toxicity following a cancer diagnosis, particularly when diagnosed with advanced cancer requiring complex multi-modality treatment.ConclusionCancer patients in Sarawak have various unmet information needs. Written information and educational videos in local indigenous languages may be more suitable for Sarawak's multi-ethnic population. Sexual aspects of care and family planning are challenging but essential topics to discuss, in particular due to the high prevalence of breast and cervical cancer amongst young women of reproductive age in Sarawak. Financial assessment and information on support services offered by government and non-government organisations should be provided to eligible patients. A holistic needs assessment of each patient at time of diagnosis and support through their cancer journey requires a multi-disciplinary team of medical, nursing and allied health professionals including clinical nurse specialists, pharmacists, counsellors, physiotherapists, occupational therapists, speech and language therapists, dieticians and social workers.

Abstract Sphaeropteris lepifera is a tree fern in the Cyatheaceae, a family that has played an important role in the evolution of plant systems. This study aimed to analyze the complete chloroplast genome of S. lepifera and compared it with previously published chloroplast genomes Cyatheaceae family. The chloroplast genome of S. lepifera comprised 162,114 bp, consisting of a large single copy (LSC) region of 86,327 bp, a small single copy (SSC) region of 27,731 bp and a pair of inverted repeats (IRa and IRb) of 24,028 bp each. The chloroplast genome encoded 129 genes, comprising 32 transfer RNAs, 8 ribosomal RNAs, and 89 protein-coding genes. Comparison of the genomes of 7 Cyatheaceae plants showed that the chloroplast genome of S. lepifera was missing the gene trnV-UAC. Expansion of the SSC region led to the difference in the chloroplast genome size of S. lepifera. Eight genes, atpI, ccsA, petA, psaB, rpl16, rpoA, rpoC1, and ycf2 have high nucleic acid diversity and can be regarded as potential molecular markers. The genes trnG-trnR and atpB were suitable for DNA barcodes between different communities of S. lepifera. The S. lepifera groups in Zhejiang Province probably diffused from Pingtan and Ningde, Fujian. The results will provide a basis for species identification, biological studies, and endangerment mechanism of S. lepifera.

Abstract Oxidative stress had been linked to hypertensive renal impairment in previous investigations. Superoxide dismutase (SOD) was a clinically available oxidative stress biomarker. The association between SOD and the microalbuminuria in hypertensive patients has not been established. From January 2017 to December 2018, data on 690 patients with essential hypertension were collected retrospectively at Shandong Provincial Qianfoshan Hospital. Patients were divided into hypertension with microalbuminuria group (HM) and hypertension without microalbuminuria group (NHM). Clinical data from patients were collected and compared between the two groups. Spearman correlation analysis was used to analyze the correlation between UACR and SOD. Univariate and multivariate logistic regression analyses were used to screen for the risk factors for HM. Our research included 556 patients in the NHM group and 134 patients in the HM group. Spearman correlation analysis showed a negative correlation between SOD and UACR (P

Abstract Background Cardiovascular disease (CVD) is the leading cause of death in China. No previous study has reported CVD mortality at county-level, and little was known about the nonmedical ecological factors of CVD mortality at such small scale in mainland China. Understanding the spatiotemporal variations of CVD mortality and examining its nonmedical ecological factors would be of great importance to tailor local public health policies. Methods By using national mortality registration data in China, this study used hierarchical spatiotemporal Bayesian model to demonstrate spatiotemporal distribution of CVD mortality in 2844 counties during 2006 to 2020 and investigate how nonmedical ecological determinants have affected CVD mortality inequities from the spatial perspectives. Results During 2006–2020, the age-standardized mortality rate (ASMR) of CVD decreased from 284.77 per 100,000 in 2006 to 241.34 per 100,000 in 2020. Among 2844 counties, 1144 (40.22%) were hot spots counties with a higher CVD mortality risk compared to the national average and located mostly in northeast, north central, and westernmost regions; on the contrary, 1551 (54.53%) were cold spots counties and located mostly in south and southeast coastal counties. CVD mortality risk decreased from 2006 to 2020 was larger in counties where CVD mortality rate had been higher in 2006 in most of the counties, vice versa. Nationwide, nighttime light intensity (NTL) was the major influencing factor of CVD mortality, a higher NTL appeared to be negatively associated with a lower CVD mortality, with one unit increase in NTL, and the CVD mortality risk will decrease 11% (relative risk of NTL was estimated as 0.89 with 95% confidence interval of 0.83–0.94). Conclusions Substantial between-county discrepancies of CVD mortality distribution were observed during past 15 years in mainland China. Nonmedical ecological determinants were estimated to significantly explain the overall and local spatiotemporal patterns of this CVD mortality risk. Targeted considerations are needed to integrate primary care with clinical care through intensifying further strategies to narrow unequally distribution of CVD mortality at local scale. The approach to county-level analysis with small area models has the potential to provide novel insights into Chinese disease-specific mortality burden.

Objective: Metformin is a widely used drug, with a good safety profile, for treatment of type 2 diabetes. Recently, it has been found to also exhibit immunomodulatory potential. We aim to preliminarily explore the potential role of metformin in regulating innate immunity using UM-HET3 mice. Methods: In this study, we treated juvenile UM-HET3 mice with metformin and investigated the alteration of the innate immune response. Peripheral blood of HET3 mice was treated with ex-vivo lipopolysaccharide (LPS) stimulation to induce a leukocyte inflammatory response, which was detected by analyzing the expression of LPS receptors TLR4 and CD14 on leukocytes with flow cytometry. Furthermore, cytokine release induced by LPS was measured in isolated cell culture supernatants with ELISA. Results: In this study LPS treatment triggered a downregulation of TLR4 as well as an upregulation of CD14 expressed on the cell surface. Besides, it enhanced the secretion of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. The results showed that metformin treatment led to a significant ( p < .05) increase in the expression of CD14 and pro-inflammatory cytokines, including IL-1β and IL-6, as well as increased proportion of TLR4 downregulation on the cell surface in response to LPS, specifically in males. Conclusions: This study indicates that treating juvenile mice with metformin enhances the innate immune response to bacterial endotoxin in males, but not in females.

Abstract Human induced pluripotent stem cell-derived kidney organoids have potential for disease modeling and to be developed into clinically transplantable auxiliary tissue. However, they lack a functional vasculature, and the sparse endogenous endothelial cells (ECs) are lost upon prolonged culture in vitro, limiting maturation and applicability. Here, we use intracoelomic transplantation in chicken embryos followed by single-cell RNA sequencing and advanced imaging platforms to induce and study vasculogenesis in kidney organoids. We show expansion of human organoid-derived ECs that reorganize into perfused capillaries and form a chimeric vascular network with host-derived blood vessels. Ligand-receptor analysis infers extensive potential interactions of human ECs with perivascular cells upon transplantation, enabling vessel wall stabilization. Perfused glomeruli display maturation and morphogenesis to capillary loop stage. Our findings demonstrate the beneficial effect of vascularization on not only epithelial cell types, but also the mesenchymal compartment, inducing the expansion of ´on target´ perivascular stromal cells, which in turn are required for further maturation and stabilization of the neo-vasculature. The here described vasculogenic capacity of kidney organoids will have to be deployed to achieve meaningful glomerular maturation and kidney morphogenesis in vitro.

Abstract Background Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients. Methods HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR). Results Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported. Conclusions Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients. Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1900021684 .

Abstract To develop and verify an automatic classification method using artificial intelligence deep learning to determine the bone mineral density level of the implant site in oral implant surgery from radiographic data obtained from cone beam computed tomography (CBCT) images. Seventy patients with mandibular dentition defects were scanned using CBCT. These Digital Imaging and Communications in Medicine data were cut into 605 training sets, and then the data were processed with data standardization, and the Hounsfiled Unit (HU) value level was determined as follows: Type 1, 1000–2000; type 2, 700–1000; type 3, 400–700; type 4, 100–400; and type 5, − 200–100. Four trained dental implant physicians manually identified and classified the area of the jaw bone density level in the image using the software LabelMe. Then, with the assistance of the HU value generated by LabelMe, a physician with 20 years of clinical experience confirmed the labeling level. Finally, the HU mean values of various categories marked by dental implant physicians were compared to the mean values detected by the artificial intelligence model to assess the accuracy of artificial intelligence classification. After the model was trained on 605 training sets, the statistical results of the HU mean values of various categories in the dataset detected by the model were almost the same as the HU grading interval on the data annotation. This new classification provides a more detailed solution to guide surgeons to adjust the drilling rate and tool selection during preoperative decision-making and intraoperative hole preparation for oral implant surgery.

Abstract Background Benign prostate hyperplasia (BPH) is the most common urological problem in elderly males. Recent studies have reported polymorphism in various metabolic genes in BPH. However, their association with the susceptibility of BPH is still inconsistent. Here, we systematically reviewed and performed a meta-analysis of CYP17, VDR, and ACE genes to determine their precise association with the risk of BPH. Methods A comprehensive literature search for published studies on candidate gene associations involving vitamin D receptor (VDR), angiotensin-converting enzyme (ACE), and CYP17 genes with the risk of BPH was done up to April 2020 in PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases. Fixed/random effects models were used to estimate the odd’s ratio (OR) and 95% confidence intervals (CIs). Begg’s funnel plot was used to assess the potential for publication bias. Results We found a total of 23 studies containing 3461 cases and 3833 controls for these gene polymorphisms. A significant association of ACE gene polymorphism was observed under the recessive (II vs. ID + DD) model for BPH susceptibility compared to control subjects (overall OR = 1.67, 95% CI = 1.03–2.73). Similar trends were observed for ACE gene polymorphism in Caucasian (OR = 6.18, 95% CI = 1.38–27.68) and Asian (OR = 1.42, 95% CI = 0.99–2.03) populations under study. No significant association was observed in VDR and CYP17 gene polymorphisms in any dominant or recessive models. Conclusion Significant OR demonstrated the implication of ACE gene polymorphism in the proliferation of prostate tissue, which in turn is associated with BPH susceptibility. However, prospective studies at large scale and sample size are needed to confirm the current findings.

Abstract Background Chinese herbal medicine is made up of hundreds of natural drug molecules and has played a major role in traditional Chinese medicine (TCM) for several thousand years. Therefore, it is of great significance to study the target of natural drug molecules for exploring the mechanism of treating diseases with TCM. However, it is very difficult to determine the targets of a fresh natural drug molecule due to the complexity of the interaction between drug molecules and targets. Compared with traditional biological experiments, the computational method has the advantages of less time and low cost for targets screening, but it remains many great challenges, especially for the molecules without social ties. Methods This study proposed a novel method based on the Cosine-correlation and Similarity-comparison of Local Network (CSLN) to perform the preliminary screening of targets for the fresh natural drug molecules and assign weights to them through a trained parameter. Results The performance of CSLN is superior to the popular drug-target-interaction (DTI) prediction model GRGMF on the gold standard data in the condition that is drug molecules are the objects for training and testing. Moreover, CSLN showed excellent ability in checking the targets screening performance for a fresh-natural-drug-molecule (scenario simulation) on the TCMSP (13 positive samples in top20), meanwhile, Western-Blot also further verified the accuracy of CSLN. Conclusions In summary, the results suggest that CSLN can be used as an alternative strategy for screening targets of fresh natural drug molecules.

Gastroesophageal reflux disease (GERD) is very common and defined as troublesome symptoms owing to excessive acid reflux. The spectrum of GERD is broad, including not only erosive esophagitis and Barrett's esophagus but also nonerosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn. Patients with reflux symptoms despite normal endoscopy remain common clinical presentation, can be heterogeneous overlapping with functional gastrointestinal disorders. Ambulatory esophageal pH monitoring with and without impedance helps the diagnosis of NERD. Metrics such as baseline impedance and postreflux swallow induced peristaltic wave enhance diagnostic accuracy in patients with inconclusive diagnoses. The major treatment of all manifestations of GERD is acid suppression with proton pump inhibitors, while other therapies, such as reflux-reducing agents and adjunctive medications, can be individualized where the response to traditional management is incomplete. GERD patients often need long-term treatment due to frequent relapses. Anti-reflux surgery can be effective too. Endoscopic therapies have some promising results, but long-term outcomes remain to be determined.

The advanced manufacturing industry is located at the top of the manufacturing value chain. Its development is restricted by supply chain collaboration (SCC), the level of which is affected by many factors. Few studies comprehensively summarize what influences SCC and distinguish the impact level of each factor. Practitioners have difficulty isolating the primary factors that affect SCC and managing them effectively. Therefore, based on synergetics and the theory of comparative advantage, this study analyzes what influences SCC in the advanced manufacturing industry and how these influencing factors work, using data from 94 manufacturing enterprises and the Haken model to identify the influencing factors. The results show that China's advanced manufacturing supply chain underwent a phase change and entered a new stage during 2017-2018. In the new stage, the competitive advantages of enterprises are one order parameter (slow variable) and are primary factors affecting SCC. The interest demands of enterprises are a fast variable and are secondary factors affecting SCC. The competitive advantages of enterprises dominate the interests of enterprises in affecting the collaboration level of China's advanced manufacturing supply chain. In addition, in the process of influencing SCC, there is a positive correlation between the competitive advantages of enterprises and the interest demands of enterprises, and the two factors have a positive feedback mechanism. Finally, when the enterprises in the supply chain cooperate based on their differential advantages, the collaboration capability of the supply chain is at the highest level, and the overall operation of the supply chain is orderly. In terms of theoretical contribution, this study is the first to propose a collaborative motivation framework that conforms to the characteristics of sequential parameters, which provides a theoretical reference for subsequent studies on SCC. In addition, the theory of comparative advantage and synergetics are linked for the first time in this study, and both of them are enriched and developed. Equally importantly, this study compares the bidirectional influence between firms' competitive advantages and firms' interest demands and the ability of both to influence SCC, enriching previous validation studies of unidirectional influence. In terms of practical implications, this study guides top managers to focus on the management practice of collaborative innovation in the supply chain and advises purchasing managers and sales managers on selecting supply chain partnerships.

In power fingerprint identification, feature information is insufficient when using a single feature to identify equipment, and small load data of specific customers, difficult to meet the refined equipment classification needs. A power fingerprint identification based on the improved voltage-current(V-I) trajectory with color encoding and transferred CBAM-ResNet34 is proposed. First, the current, instantaneous power, and trajectory momentum information are added to the original V-I trajectory image using color coding to obtain a color V-I trajectory image. Then, the ResNet34 model was pre-trained using the ImageNet dataset and a new fully-connected layer meeting the device classification goal was used to replace the fully-connected layer of ResNet34. The Convolutional Block Attention Module (CBAM) was added to each residual structure module of ResNet34. Finally, Class-Balanced (CB) loss is introduced to reweight the Softmax cross-entropy (SM-CE) loss function to solve the problem of data imbalance in V-I trajectory identification. All parameters are retrained to extract features from the color V-I trajectory images for device classification. The experimental results on the imbalanced PLAID dataset verify that the method in this paper has better classification capability in small sample imbalanced datasets. The experimental results show that the method effectively improves the identification accuracy by 4.4% and reduces the training time of the model by 14 minutes compared with the existing methods, which meets the accuracy requirements of fine-grained power fingerprint identification.

A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2, and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17, respectively. Here, we developed a new method to induce Tfh1, Tfh2, and Tfh17-like (iTfh1, iTfh2, and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.

Abstract With the optimal operating cost and optimal carbon emission target of the chemical logistics companies, a low-carbon routing optimisation with a multi-energy type vehicle combined problem is proposed by considering the concept of the logistics companies’ low-carbon behaviour. An integrated decision-making of multi-energy type vehicles combined strategy and route optimisation based on customer demand is presented, and an improved genetic algorithm is designed. A case study is then applied based on the data collected from the case research. The effectiveness of the improved genetic algorithm is tested. The two joint objectives of operating cost and carbon emission are examined through the cost analysis of environmental energy vehicles and traditional energy vehicles in different combination scenarios. The case analysis shows that a rational multi-energy type vehicle combination with route optimisation has a significant correlation with the operating cost and carbon emissions, while the environmental vehicle purchasing cost reduction and subsidy policy affect the operating cost.

Abstract. Background:. Colorectal cancer (CRC) is the fourth cause of cancer death in China. We aimed to provide national and subnational estimates and changes of CRC premature mortality burden during 2005–2020. Methods:. Data from multi-source on the basis of the national surveillance mortality system were used to estimate mortality and years of life lost (YLL) of CRC in the Chinese population during 2005–2020. Estimates were generated and compared for 31 provincial-level administrative divisions in China. Results:. Estimated CRC deaths increased from 111.41 thousand in 2005 to 178.02 thousand in 2020; age-standardized mortality rate decreased from 10.01 per 100,000 in 2005 to 9.68 per 100,000 in 2020. Substantial reduction in CRC premature mortality burden, as measured by age-standardized YLL rate, was observed with a reduction of 10.20% nationwide. Marked differences were observed in the geographical patterns of provincial units, and they appeared to be obvious in areas with higher economic development. Population aging was the dominant driver which contributed to the increase in CRC deaths, followed by population growth and age-specific mortality change. Conclusions:. Substantial discrepancies were observed in the premature mortality burden of CRC across China. Targeted considerations were needed to promote a healthy lifestyle, expand cost-effective CRC early screening and diagnosis, and improve medical treatment to reduce CRC mortality among high-risk populations and regions with inadequate healthcare resources.

Abstract This study aims to investigate the reliability and efficacy of maximum fluorescein tear break-up time (FTBUTmax) in diagnosing dry eye disease (DED). 147 participants were enrolled in this study. Ocular symptoms were assessed by Ocular Surface Disease Index (OSDI). The fluorescein tear break-up time (FTBUT) examination, corneal fluorescein staining (CFS), and Schirmer I test were performed on both eyes. Each participant underwent 3 consecutive FTBUT tests, and five types of FTBUT values including FTBUTmax, the minimum FTBUT (FTBUTmin), the first FTBUT (FTBUT1), the average of three FTBUTs (FTBUT123) and the average of the first and second FTBUT (FTBUT12) were recorded. FTBUTmax was larger than the other FTBUT values, but no differences were found among the values of FTBUT1, FTBUT123, FTBUT12 and FTBUTmin. In the ROC analysis, FTBUTmax had the largest or the second largest area under the ROC (AUROC) in all three DED diagnostic criteria, while FTBUTmin had the least AUROC of them. ROC efficacy of FTBUTmax was significantly higher than that of FTBUT123, FTBUT12, FTBUT1 and FTBUTmin in the OSDI criteria and higher than that of FTBUT1 and FTBUTmin in Schirmer I test and CFS tests. FTBUTmax has a close correlation with OSDI, Schirmer I test and CFS, and is an effective tool for the DED diagnosis.

Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the TME.

Abstract Background Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus. The main symptoms of DPN include numbness or pain in both extremities and paresthesia (such as formication or burning sensations), which greatly affect patients’ quality of life. Pharmacological treatments for DPN are associated with both uncertain therapeutic effects and adverse effects, as well as with high costs. Some clinical studies have reported that low-level laser therapy (LLLT) relieves clinical symptoms and improves nerve function in patients with DPN. We intend to conduct a systematic review and meta-analysis to further evaluate the effectiveness and safety of LLLT for DPN. Methods The following electronic databases will be searched to retrieve literature from their inception until December 2020: MEDLINE (PubMed), Embase, Cochrane Central Register of Controlled Trials, Web of Science (the Science and Social Science Citation Index), CNKI, VIP, WanFang, and SinoMed. Simultaneously, clinical registration tests and gray literature will also be retrieved. Randomized controlled trials (RCTs) comparing LLLT with either sham LLLT, no (specific) treatment, or active conventional medical treatments will be included. The primary outcomes will be nerve conduction velocity as well as clinical scores that assess neurological function and related symptoms. The risk of bias of each study and quality of evidence will be assessed using the updated Cochrane Risk of Bias 2.0 tool and GRADE approach, respectively. A meta-analysis will then be conducted using Review Manager software version 5.3. Discussion This study will integrate RCTs and analyze data to provide a detailed summary of the evidence relating to the effects and safety of LLLT in patients with DPN. LLLT will be compared with sham LLLT, no (specific) treatment, or active conventional medical treatments, especially in terms of neurological function, quality of life, and adverse events. In conclusion, this systematic review will generate evidence regarding the use of LLLT to treat DPN, in terms of both its efficacy and safety. Systematic review registration This protocol was registered with the International Prospective Register of Systematic Reviews on April 2020 (registration number: CRD42020170625 ).

Abstract To determine the factors predicting the probability of severe postpartum hemorrhage (SPPH) in women undergoing repeat cesarean delivery (RCD). This multicenter, retrospective cohort study involved women who underwent RCD from January 2017 to December 2017, in 11 public tertiary hospitals within 7 provinces of China. The all-variables model and the multivariable logistic regression model (pre-operative, operative and simple model) were developed to estimate the probability of SPPH in development data and external validated in validation data. Discrimination and calibration were evaluated and clinical impact was determined by decision curve analysis. The study consisted of 11,074 women undergoing RCD. 278 (2.5%) women experienced SPPH. The pre-operative simple model including 9 pre-operative features, the operative simple model including 4 pre-operative and 2 intraoperative features and simple model including only 4 closely related pre-operative features showed AUC 0.888, 0.864 and 0.858 in development data and 0.921, 0.928 and 0.925 in validation data, respectively. Nomograms were developed based on predictive models for SPPH. Predictive tools based on clinical characteristics can be used to estimate the probability of SPPH in patients undergoing RCD and help to allow better preparation and management of these patients by using a multidisciplinary approach of cesarean delivery for obstetrician.

Chloroquine and hydroxychloroquine are both classic 4-aminoquinoline antimalarial drugs with similar chemical structures and mechanisms of action. As the toxicity and side effects of hydroxychloroquine are lower than those of chloroquine, hydroxychloroquine is the main clinical application at present, with good efficacy and safety. Chloroquine and hydroxychloroquine are widely used in the clinic because of their immunosuppressive, anti-inflammatory, antiviral, antitumor and photoprotective effects. The main mechanisms by which chloroquine/hydroxychloroquine inhibits immunity include inhibiting lysosome activity, autophagy, immune response signaling pathways production of proinflammatory cytokines. Chloroquine stabilizes the lysosomal membrane and reduces the release of lysosomal enzymes. As a prostaglandin antagonist, chloroquine can reduce the production of prostaglandins and leukotrienes, thus playing an anti-inflammatory role. Chloroquine/hydroxychloroquine can inhibit virus proliferation in the early stage of virus replication by inhibiting the glycosylation of the angiotensin converting enzyme 2 receptor. At present, hydroxychloroquine has been found to have significant efficacy in discoid lupus erythematosus, oral lichen planus, chronic cheilitis, pemphigus foliaceus, Sjögren’s syndrome and other stomatological diseases. However, eye damage is the most important adverse reaction of hydroxychloroquine, and its occurrence is related to the cumulative dose of drugs.

We describe the characterization of a novel fish leech species found on the gills of bighead carp (Hypophthalmichthys nobilis) from lakes and reservoirs in China. This leech is morphologically similar to Limnotrachelobdella sinensis recorded on goldfish and common carp. However, there are 0–2 pairs of symmetrical or asymmetrical eyes and 10 pairs of pulsatile vesicles in the newly discovered leech, in remarkable contrast to L. sinensis. Except for bighead carp, where it demonstrated a higher than 90% prevalence, and silver carp (H. molitrix), where there was low infection, this leech was not detected on any other fish from the Qiandao reservoir in China that were examined during this investigation. Molecular analyses indicated 87.8% ITS sequence identity with L. sinensis and 85.0 and 86.1% COX1 sequence identity with L. sinensis and L. okae, respectively. The uncorrected p-distance based on the COX1 sequence was found to be 15.1 and 14.0% for L. sinensis and L. okae, respectively, suggesting interspecific variation. Phylogenetic analyses based on the combination of 18S and COX1 sequences showed that the newly discovered leech groups with Limnotrachelobdella species. Histopathological observation indicated that attachment of the leech on the gill rakers and gill arches causes a loss of connective tissue, hemorrhage, and ulceration. Based on the morphology, molecular analyses, and host specificity, we conclude that this leech is a new species of Limnotrachelobdella and named it Limnotrachelobdella hypophthalmichthysa n. sp.

Abstract The North Pacific subtropical gyre (NPSG) plays a major role in present global ocean circulation. At times, the gyre has coursed through the South China Sea, but its role in the evolutionary development of that Sea remains uncertain. This work systematically describes a major shift in NPSG paleo-circulation evident from sedimentary features observed in seismic and bathymetric data. These data outline two contourite depositional systems—a buried one formed in the late Miocene, and a latest Miocene to present-day system. The two are divided by a prominent regional discontinuity that represents a major shift in paleo-circulation during the latest Miocene (~ 6.5 Ma). The shift coincides with the further restriction of the South China Sea with respect to the North Pacific due to the formation of the Luzon Strait as a consequence of further northwest movement of the Philippine Sea plate. Before that restriction, data indicate vigorous NPSG circulation in the South China Sea. Semi-closure, however, established a new oceanographic circulation regime in the latest Miocene. This work demonstrates the significant role of recent plate tectonics, gateway development, and marginal seas in the establishment of modern global ocean circulation.

Background: Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNA sequencing (scRNAseq) technologies has enabled a new approach to investigate SGCs. Methods: In this study we used scRNAseq to investigate SGCs from mice subjected to sciatic nerve injury. We used a meta-analysis approach to compare the injury response with that found in other published datasets. Furthermore, we also used scRNAseq to investigate how cells from the dorsal root ganglion (DRG) change after 3 days in culture. Results: From our meta-analysis of the injured conditions, we find that SGCs share a common signature of 18 regulated genes following sciatic nerve crush or sciatic nerve ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state while others start resembling Schwann cell-like precursors. Conclusion: By using integrated analyses of new and previously published scRNAseq datasets, this study provides a consensus view of which genes are most robustly changed in SGCs after injury. Our results are available via the Broad Institute Single Cell Portal, so that readers can explore and search for genes of interest.

In order to deepen the standardized training of residents in ultrasound medicine department and improve the comprehensive quality and core competence of residents.Aimed at the blind points in current teaching methods, we have sorted out the teaching and training needs of resident in the form of questionnaire survey and carried out “order dishes style” morning courses. According to the feedback from the residents, the morning course mainly includes four topics include clinical skills, scientific research topics, doctor-patient communication and humanistic literacy as well as the examination for practicing physicians. In addition, we have adopted the stratified curriculum arrangement and training plan according to the different educational background of the residents. The setting of the morning course makes use of the fragment time in the morning can not only help to coordinate the work and study schedule of teachers and residents but also help to alleviate the contradiction between work and study and contribute to improve the comprehensive quality of residents and the teaching quality.

The analysis of pathological images, such as cell counting and nuclear morphological measurement, is an essential part in clinical histopathology researches. Due to the diversity of uncertain cell boundaries after staining, automated nuclei segmentation of Hematoxylin-Eosin (HE) stained pathological images remains challenging. Although better performances could be achieved than most of classic image processing methods do, manual labeling is still necessary in a majority of current machine learning based segmentation strategies, which restricts further improvements of efficiency and accuracy. Aiming at the requirements of stable and efficient high-throughput pathological image analysis, an automated Feature Global Delivery Connection Network (FGDC-net) is proposed for nuclei segmentation of HE stained images. Firstly, training sample patches and their corresponding asymmetric labels are automatically generated based on a Full Mixup strategy from RGB to HSV color space. Secondly, in order to add connections between adjacent layers and achieve the purpose of feature selection, FGDC module is designed by removing the jumping connections between codecs commonly used in UNet-based image segmentation networks, which learns the relationships between channels in each layer and pass information selectively. Finally, a dynamic training strategy based on mixed loss is used to increase the generalization capability of the model by flexible epochs. The proposed improvements were verified by the ablation experiments on multiple open databases and own clinical meningioma dataset. Experimental results on multiple datasets showed that FGDC-net could effectively improve the segmentation performances of HE stained pathological images without manual interventions, and provide valuable references for clinical pathological analysis.

Biomedical research is inseparable from the analysis of various histopathological images, and hematoxylin-eosin (HE)-stained images are one of the most basic and widely used types. However, at present, machine learning based approaches of the analysis of this kind of images are highly relied on manual labeling of images for training. Fully automated processing of HE-stained images remains a challenging task due to the high degree of color intensity, size and shape uncertainty of the stained cells. For this problem, we propose a fully automatic pixel-wise semantic segmentation method based on pseudo-labels, which concerns to significantly reduce the manual cell sketching and labeling work before machine learning, and guarantees the accuracy of segmentation. First, we collect reliable training samples in a unsupervised manner based on K-means clustering results; second, we use full mixup strategy to enhance the training images and to obtain the U-Net model for the nuclei segmentation from the background. The experimental results based on the meningioma pathology image dataset show that the proposed method has good performance and the pathological features obtained statistically based on the segmentation results can be used to assist in the clinical grading of meningiomas. Compared with other machine learning strategies, it can provide a reliable reference for clinical research more effectively.

Objective To assess the effect of PBL on OSCE results of residents in ultrasound department. Methods There were 30 trainees from class 2015 and class 2016 for standardized resident training. Fourteen residents from class 2015 received traditional teaching methods and 16 residents from class 2016 received traditional teaching method combined with PBL. The scores of Objective Structured Clinical Examination(OSCE) between the two groups were compared and analyzed to find whether PBL can improve the OSCE results of residents in our department. Results The scores of OSCE including practice and theory of class 2016 were significantly higher than that of class 2015(P＜0.05). Conclusions PBL may improve the practical skill and theory level of residents and optimize their professional capacity.

Objective To explore the relationship between psychological factors and recurrent aphthous ulcer (RAU), oral lichen planus (OLP), and burning mouth syndrome (BMS) and to provide a reference for clinical diagnosis and treatment of the disease. Methods From July to October 2018, 50 patients with common RAU, refractory RAU, OLP and BMS were selected as the observation group, and 50 healthy participants without major systemic diseases and oral mucosal diseases matched for age and sex served as the control group. The psychological status of the subjects in each group was investigated by questionnaires, including the generalized anxiety disorder 7⁃item scale(GAD⁃7) and the patient health questionnaire⁃9 (PHQ⁃9). Results Compared with the control group, the PHQ⁃9 scores in the refractory RAU, common RAU, OLP and BMS groups were higher than those in the control group (P < 0.05), and the GAD⁃ 7 scores in the refractory RAU, OLP and BMS groups were higher than those in the control group (P < 0.05). In the RAU group, the GAD⁃7 score of intractable RAU was higher than that of common RAU (P < 0.05), and there was no signifi⁃ cant difference in the PHQ⁃9 score (P > 0.05). Conclusion RAU, OLP and BMS are common psychosomatic diseases presented by patients in the Department of Oral Mucosal Diseases. Their occurrence and development are related to the psychological status of patients. A tendency toward anxiety is significantly more common among refractory RAU patients than common RAU patients

Background: DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gliomas with DDR alterations and elucidate the biological process of DDR alterations that regulate the cross talk between gliomas and the tumor microenvironment. Methods: Integrated transcriptomic and genomic analyses were undertaken to conduct a comprehensive investigation of the role of DDR alterations in glioma. The prognostic DDR-related cytokines were identified from multiple datasets. In vivo and in vitro experiments validated the role of p53, the key molecule of DDR, regulating M2 polarization of microglia in glioma. Findings: DDR alterations are associated with clinical and molecular characteristics of glioma. Gliomas with DDR alterations exhibit distinct immune phenotypes, and immune cell types and cytokine processes. DDR-related cytokines have an unfavorable prognostic implication for GBM patients and are synergistic with DDR alterations. Overexpression of MDK mediated by p53, the key transcriptional factor in DDR pathways, remodels the GBM immunosuppressive microenvironment by promoting M2 polarization of microglia, suggesting a potential role of DDR in regulating the glioma microenvironment. Interpretation: Our work suggests that DDR alterations significantly contribute to remodeling the glioma microenvironment via regulating the immune response and cytokine pathways. Fund: This study was supported by: 1. The National Key Research and Development Plan (No. 2016YFC0902500); 2. National Natural Science Foundation of China (No. 81702972, No. 81874204, No. 81572701, No. 81772666); 3. China Postdoctoral Science Foundation (2018M640305); 4. Special Fund Project of Translational Medicine in the Chinese-Russian Medical Research Center (No. CR201812); 5. The Research Project of the Chinese Society of Neuro-oncology, CACA (CSNO-2016-MSD12); 6. The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2017–201); and 7. Harbin Medical University Innovation Fund (2017LCZX37, 2017RWZX03). Keywords: DNA damage repair, Microglia, Glioma microenvironment, p53, Midkine

Objective: Sclerostin is a canonical Wingless (Wnt)/β-catenin signaling pathway inhibitor and had been associated with high arterial stiffness in patients with chronic kidney disease. The aortic augmentation index (AIx), a noninvasive method of assessing central hemodynamics/wave reflections, has been widely used as a clinical index of arterial stiffness. The aim of this study was to evaluate the relationship between fasting serum sclerostin levels and AIx values in peritoneal dialysis (PD) patients. Materials and Methods: Fasting blood samples were obtained from 75 PD patients. The aortic AIx value was measured using a validated tonometry system (SphygmoCor, AtCor Medical, Sydney, New South Wales, Australia). Serum sclerostin and dickkopf-1 (DKK1) levels were quantified using commercial enzyme-linked immunosorbent assay kits. Results: Women PD patients had higher aortic AIx values than men (P = 0.039), while lower aortic AIx values were found in PD patients who used statins (P = 0.004). Univariate linear analysis of the aortic AIx values in PD patients showed that systolic blood pressure (P = 0.001), diastolic blood pressure (P = 0.018), and serum sclerostin levels (P = 0.001) were positively correlated, while height (P = 0.018), body weight (P = 0.001), body mass index (P = 0.043), and weekly total creatinine clearance (P = 0.015) were negatively correlated with aortic AIx values in PD patients. Multivariate linear regression analysis of the factors significantly associated with the aortic AIx values showed that serum sclerostin levels (adjusted R2 = 0.057, P = 0.011) and systolic blood pressure (adjusted R2 = 0.125, P = 0.004) were positively associated, while body weight (adjusted R2 = 0.113, P = 0.002) was inversely associated with aortic AIx values in PD patients. Conclusion: In this study, the serum sclerostin level, but not DKK1, was positively associated with aortic AIx values in PD patients.

Abstract Background Urine has evolved as a promising body fluids in clinical proteomics because it can be easily and noninvasively obtained and can reflect physiological and pathological status of the human body. Many efforts have been made to characterize more urinary proteins in recent years, but few have focused on the analysis throughput and detection reproducibility. Increasing the urine proteomic profiling throughput and reproducibility is urgently needed for discovering potential biomarker in large cohorts. Methods In this study, we developed a fast and robust workflow for streamlined urinary proteome analysis. The workflow integrate highly efficient sample preparation technique and urinary specific data-independent acquisition (DIA) approach. The performance of the workflow was systematically evaluated and the workflow was subsequently applied in a proof-of-concept urine proteome study of 21 kidney cancer (KC) patients and 22 healthy controls. Results With this workflow, the entire sample preparation process takes less than 3 h and allows multiplexing on standard centrifuges. Without pre-fractionation, our newly developed DIA method allows quantitative analysis of ~ 1000 proteins within 80 min of MS time (~ 15 samples/day). The quantitation accuracy of the whole workflow was excellent with median CV of 9.1%. The preliminary study on KC identified 125 significantly changed proteins. Conclusions The result suggested the feasibility of applying the high throughput workflow in extensive urinary proteome profiling and clinical relevant biomarker discovery.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, with unmet need for the pharmacological therapy. The functions of ATXN7L3 in HCC progression are not known. Methods: RNA sequence, quantitative real-time PCR, and western blot were performed to detect gene expression. Chromatin immunoprecipitation was performed to detect possible mechanisms. Immunohistochemical stain was performed to examine the protein expression. Colony formation, cell growth curve and xenograft tumor experiments were performed to examine cell growth in vitro and in vivo. Findings: ATXN7L3 functions as a coactivator for ERα-mediated transactivation in HCC cells, thereby contributing to enhanced SMAD7 transcription. ATXN7L3 is recruited to the promoter regions of SMAD7 gene, thereby regulating histone H2B ubiquitination level, to enhance the transcription of SMAD7. A series of genes regulated by ATXN7L3 were identified. Moreover, ATXN7L3 participates in suppression of tumor growth. In addition, ATXN7L3 is lower expressed in HCC samples, and the lower expression of ATXN7L3 positively correlates with poor clinical outcome in patients with HCC. Interpretation: This study demonstrated that ATXN7L3 is a novel regulator of SMAD7 transcription, subsequently participating in inhibition of tumor growth in HCC, which provides an insight to support a previously unknown role of ATXN7L3 in HCC progression. Fund: This work was funded by 973 Program Grant from the Ministry of Science and Technology of China (2013CB945201), National Natural Science Foundation of China (31871286, 81872015, 31701102, 81702800, 81902889), Foundation for Special Professor of Liaoning Province, Natural Science Foundation of Liaoning Province (No.20180530072); China Postdoctoral Science Foundation (2019M651164).

Although lung cancer is one of the greatest threats to human health, its signaling pathway and related genes are still unknown. This study integrates data from three groups of people to study potential key candidate genes and pathways related to lung cancer. Expression profiles (GSE18842, GSE19188 and GSE27262), including 162 tumor tissue and 135 adjacent normal lung tissue samples, were integrated and analyzed. Differentially expressed genes (DEGs) and candidate genes were identified, their expression pathways were analyzed, and the diethylene glycol-related protein–protein interaction (PPI) network was analyzed. We identified 232 shared DEGs (40 upregulated and 192 down-regulated) from the three GSE datasets. The DEGs were clustered according to function and signaling pathway for significant enrichment analysis. In total, 129 nodes/DEGs were identified from the DEG PPI network complex. An improved prognosis was associated with increased Helicase, Lymphoid-Specific (HELLS) and decreased Intercellular adhesion molecule 1 (ICAM1) mRNA expression in lung cancer patients. In conclusion, we used integrated bioinformatics analysis to identify candidate genes and pathways in lung cancer to show that HELLS and ICAM1 might be the key genes related to tumorigenesis or tumor progression in lung cancer. Additional studies are needed to further explore the involved functional mechanisms.

The purpose of this research is to solve the problems of unreasonable layout of the production plant, disorder of the logistics process, and unbalanced production line in discrete manufacturing plants. By analyzing the production process and characteristics, the timed Petri net model is constructed according to the function and connection of each production unit, which is then used to generate a FlexSim simulation model of the production plant logistics system with a simulation software. Therewith the FlexSim simulation model is used to simulate the original layout of the plant, and to analyse the simulation data synthetically to put forward an improvement strategy. Combined with the use of the systematic layout planning method to analyze the overall layout of the plant and logistics relations, we infer the relevant drawings between the production units and determine the improved layout of the facilities. Finally, by comparing the before and after improvement simulation results, it is verified that the combination of timed Petri nets and systematic layout planning is effective to ameliorate the layout of the plant facilities and the logistics system. This method makes up for the factors that traditional methods have not considered, achieves the goal of reducing the cross circuitous route of the plant and the idle rate of equipment, and improving the efficiency of production.