Global status and trends of metabolomics in diabetes: A literature visualization knowledge graph study.

BACKGROUND: Diabetes is a metabolic disease characterized by hyperglycemia, which has increased the global medical burden and is also the main cause of death in most countries. AIM: To understand the knowledge structure of global development status, research focus, and future trend of the relationship between diabetes and metabolomics in the past 20 years. METHODS: The articles about the relationship between diabetes and metabolomics in the Web of Science Core Collection were retrieved from 2002 to October 23, 2023, and the relevant information was analyzed using CiteSpace6.2.2R (CiteSpace), VOSviewer6.1.18 (VOSviewer), and Bibliometrix software under R language. RESULTS: A total of 3123 publications were included from 2002 to 2022. In the past two decades, the number of publications and citations in this field has continued to increase. The United States, China, Germany, the United Kingdom, and other relevant funds, institutions, and authors have significantly contributed to this field. Scientific Reports and PLoS One are the journals with the most publications and the most citations. Through keyword co-occurrence and cluster analysis, the closely related keywords are "insulin resistance", "risk", "obesity", "oxidative stress", "metabolomics", "metabolites" and "biomarkers". Keyword clustering included cardiovascular disease, gut microbiota, metabonomics, diabetic nephropathy, molecular docking, gestational diabetes mellitus, oxidative stress, and insulin resistance. Burst detection analysis of keyword depicted that "Gene", "microbiota", "validation", "kidney disease", "antioxidant activity", "untargeted metabolomics", "management", and "accumulation" are knowledge frontiers in recent years. CONCLUSION: The relationship between metabolomics and diabetes is receiving extensive attention. Diabetic nephropathy, diabetic cardiovascular disease, and kidney disease are key diseases for future research in this field. Gut microbiota, molecular docking, and untargeted metabolomics are key research directions in the future. Antioxidant activity, gene, validation, mass spectrometry, management, and accumulation are at the forefront of knowledge frontiers in this field.

The pattern of tumor progression on first-line immune checkpoint inhibitor-based systemic therapy for Chinese advanced hepatocellular carcinoma -CLEAP 004 study.

Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Construction of an immune-related gene signature for overall survival prediction and immune infiltration in gastric cancer.

BACKGROUND: Treatment options for patients with gastric cancer (GC) continue to improve, but the overall prognosis is poor. The use of PD-1 inhibitors has also brought benefits to patients with advanced GC and has gradually become the new standard treatment option at present, and there is an urgent need to identify valuable biomarkers to classify patients with different characteristics into subgroups. AIM: To determined the effects of differentially expressed immune-related genes (DEIRGs) on the development, prognosis, tumor microenvironment (TME), and treatment response among GC patients with the expectation of providing new biomarkers for personalized treatment of GC populations. METHODS: Gene expression data and clinical pathologic information were downloaded from The Cancer Genome Atlas (TCGA), and immune-related genes (IRGs) were searched from ImmPort. DEIRGs were extracted from the intersection of the differentially-expressed genes (DEGs) and IRGs lists. The enrichment pathways of key genes were obtained by analyzing the Kyoto Encyclopedia of Genes and Genomes (KEGGs) and Gene Ontology (GO) databases. To identify genes associated with prognosis, a tumor risk score model based on DEIRGs was constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression. The tumor risk score was divided into high- and low-risk groups. The entire cohort was randomly divided into a 2:1 training cohort and a test cohort for internal validation to assess the feasibility of the risk model. The infiltration of immune cells was obtained using 'CIBERSORT,' and the infiltration of immune subgroups in high- and low-risk groups was analyzed. The GC immune score data were obtained and the difference in immune scores between the two groups was analyzed. RESULTS: We collected 412 GC and 36 adjacent tissue samples, and identified 3627 DEGs and 1311 IRGs. A total of 482 DEIRGs were obtained. GO analysis showed that DEIRGs were mainly distributed in immunoglobulin complexes, receptor ligand activity, and signaling receptor activators. KEGG pathway analysis showed that the top three DEIRGs enrichment types were cytokine-cytokine receptors, neuroactive ligand receptor interactions, and viral protein interactions. We ultimately obtained an immune-related signature based on 10 genes, including 9 risk genes (LCN1, LEAP2, TMSB15A mRNA, DEFB126, PI15, IGHD3-16, IGLV3-22, CGB5, and GLP2R) and 1 protective gene (LGR6). Kaplan-Meier survival analysis, receiver operating characteristic curve analysis, and risk curves confirmed that the risk model had good predictive ability. Multivariate COX analysis showed that age, stage, and risk score were independent prognostic factors for patients with GC. Meanwhile, patients in the low-risk group had higher tumor mutation burden and immunophenotype, which can be used to predict the immune checkpoint inhibitor response. Both cytotoxic T lymphocyte antigen4+ and programmed death 1+ patients with lower risk scores were more sensitive to immunotherapy. CONCLUSION: In this study a new prognostic model consisting of 10 DEIRGs was constructed based on the TME. By providing risk factor analysis and prognostic information, our risk model can provide new directions for immunotherapy in GC patients.

Significant effect of posterior line treatment of HER2 positive advanced gastric cancer: A case report.

At present, there are few options for third line and above treatment of advanced gastric cancer and the single drug effect is poor. HER2 positive gastric cancer is an important subtype of gastric cancer and has certain immune characteristics. The combination of HER2 inhibitor and PD-1 inhibitor has a synergistic effect, and anti-tumor drugs targeting HER2 can play an anti-angiogenesis role by downregulating VEGF. We report a patient with HER2-positive gastric cancer who developed post-operative tumor recurrence and metastasis after adjuvant chemotherapy and radiotherapy. Trastuzumab combined with albumin paclitaxel was used as second-line treatment with progression-free survival for 9 months. In third line treatment, we retained trastuzumab and combined it with camrelizumab and apatinib. During the treatment period, although the patient stopped taking the drugs due to the side effects of camrelizumab and apatinib, he achieved a PFS of 10.4 months. Considering the good effect of the third line treatment, we added another PD-1 inhibitor and continued to combine trastuzumab treatment. We found that the patient still benefited from the treatment and continued to survive for another 4 months. At present, the patient is treated with DisitamabVedotin (HER2-ADC) combined with PD-1 inhibitor, and no overall survival outcome has been observed.

In silico genome-wide analysis of homeodomain-leucine zipper transcription factors in Cannabis sativa L.

HD-Zip (Homeodomain-Leucine Zipper) is a family of transcription factors unique to higher plants and plays a vital role in plant growth and development. Increasing research results show that HD-Zip transcription factors are widely involved in many life processes in plants. However, the HD-Zip transcription factor for cannabis, a valuable crop, has not yet been identified. The sequence characteristics, chromosome localization, system evolution, conservative motif, gene structure, and gene expression of the HD-Zip transcription factor in the cannabis genome were systematically studied. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to verify its function. The results showed that cannabis contained 33 HD-Zip gene members. The number of amino acids is 136-849aa, the isoelectric point is 4.54-9.04, and the molecular weight is 23264.32-93147.87Da. Many cis-acting elements are corresponding to hormone and abiotic stress in the HD-Zip family promoter area of cannabis. Sequencing of the transcriptome at 5 tissue sites of hemp, stems, leaves, bracts, and seeds showed similar levels of expression of 33 members of the HD-Zip gene family at 5 tissue sites. Bioinformatics results show that HD-Zip expression is tissue-specific and may be influenced by hormones and environmental factors. This lays a foundation for further research on the gene function of HD-Zip.

Liver Lipidomics Analysis Revealed the Protective mechanism of Zuogui Jiangtang Qinggan Formula in type 2 diabetes mellitus with non-alcoholic fatty liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic steatosis, a hallmark of non-alcoholic fatty liver disease (NAFLD), represents a significant global health issue. Liver lipidomics has garnered increased focus recently, highlighting Traditional Chinese Medicine's (TCM) role in mitigating such conditions through lipid metabolism regulation. The Zuogui Jiangtang Qinggan Formula (ZGJTQGF), a longstanding TCM regimen for treating Type 2 Diabetes Mellitus (T2DM) with NAFLD, lacks a definitive mechanism for its lipid metabolism regulatory effects. AIM OF THE STUDY: This research aims to elucidate ZGJTQGF's mechanism on lipid metabolism in T2DM with NAFLD. MATERIALS AND METHODS: The study, utilized db/db mice to establish T2DM with NAFLD models. Evaluations included Hematoxylin-Eosin (HE) and Oil Red O stainedstaining of liver tissues, alongside biochemical lipid parameter analysis. Liver lipidomics and Western blotting further substantiated the findings, systematically uncovering the mechanism of action mechanism. RESULTS: ZGJTQGF notably reduced body weight, and Fasting Blood Glucose (FBG), enhancing glucose tolerance in db/db mice. HE, and Oil Red O staining, complemented by biochemical and liver lipidomics analyses, confirmed ZGJTQGF's efficacy in ameliorating liver steatosis and lipid metabolism anomalies. Lipidomics identified 1571 significantly altered lipid species in the model group, primarily through the upregulation of triglycerides (TG) and diglycerides (DG), and the downregulation of phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Post-ZGJTQGF treatment, 496 lipid species were modulated, with increased PC and PE levels and decreased TG and DG, showcasing significant lipid metabolism improvement in T2DM with NAFLD. Moreover, ZGJTQGF's influence on lipid synthesis-related proteins was observed, underscoring its anti-steatotic impact through liver lipidomic alterations and offering novel insights into hepatic steatosis pathogenesis. CONCLUSIONS: Liver lipidomics analysis combined with protein verification further demonstrated that ZGJTQGF could ameliorate the lipid disturbance of TG, DG, PC, PE in T2DM with NAFLD, as well as improve fatty acid and cholesterol synthesis and metabolism through De novo lipogenesis pathway.

Mechanism of dexmedetomidine protection against cisplatin induced acute kidney injury in rats.

OBJECTIVE: This study explored the molecular mechanisms by which dexmedetomidine (Dex) alleviates cisplatin (CP)-induced acute kidney injury (AKI) in rats. METHODS: CP-induced AKI models were established, and Dex was intraperitoneally injected at different concentrations into rats in the model groups. Subsequently, rats were assigned to the control, CP, CP + Dex 10 µg/kg, and CP + Dex 25 µg/kg groups. After weighing the kidneys of the rats, the kidney arterial resistive index was calculated, and CP-induced AKI was evaluated. In addition, four serum biochemical indices were measured: histopathological damage in rat kidneys was detected; levels of inflammatory factors, interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor alpha, in kidney tissue homogenate of rats were assessed through enzyme-linked immunosorbent assay (ELISA); and levels of NLRP-3, caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N in kidney tissues of rats were determined via western blotting. RESULTS: Dex treatment reduced nephromegaly and serum clinical marker upregulation caused by CP-induced AKI. In addition, hematoxylin and eosin staining revealed that Dex treatment relieved CP-induced kidney tissue injury in AKI rats. ELISA analyses demonstrated that Dex treatment reduced the upregulated levels of proinflammatory cytokines in the kidney tissue of AKI rats induced by CP, thereby alleviating kidney tissue injury. Western blotting indicated that Dex alleviated CP-induced AKI by inhibiting pyroptosis mediated by NLRP-3 and caspase-1. CONCLUSION: Dex protected rats from CP-induced AKI, and the mechanism may be related to NLRP-3/Caspase-1-mediated pyroptosis.

Clinical outcomes following direct anterior approach during total hip arthroplasty without hip extension: a retrospective comparative study.

BACKGROUND: Traditional total hip arthroplasty (THA) using the direct anterior approach (DAA) requires a hip extension. This study aimed to compare the clinical outcomes of patients undergoing THA with DAA using either the no hip extension (NHE) or the traditional hip extension (THE) strategy. METHODS: A retrospective analysis of demographics, clinical and radiological outcomes, and occurrence of complications was performed using data from 123 patients treated between January 2020 and November 2021. The patients were categorised into two groups: NHE (84 patients) and THE (39 patients). RESULTS: The NHE group exhibited shorter operative time and had more male participants with higher ages. Comparable outcomes were observed in the visual analogue scale, Harris Hip, and Oxford Hip scores at the final follow-up. Furthermore, complications were observed in the NHE and THE groups, including two and one greater trochanteric fractures and three and one transfusions, respectively. CONCLUSIONS: Compared to the THE, employing the NHE strategy during THA with DAA in elderly and young female patients resulted in comparable clinical outcomes with several advantages, such as favourable surgical time. The NHE method also exhibited good safety and effectiveness. Therefore, the NHE strategy may be a favourable option for elderly and young female patients.

Preventing thermal aggregation of ovalbumin through dielectric-barrier discharge plasma treatment and enhancing its emulsification properties.

The impact of Dielectric-Barrier Discharge (DBD) plasma treatment on the prevention of heat-induced aggregation of Ovalbumin (OVA) and improvement in emulsification properties was investigated. Results highlighted the effective inhibition of thermal aggregation of OVA following exposure to plasma. Structural analysis revealed that the plasma-induced oxidation of sulfhydryl and intermolecular disulfide bonds played a pivotal role in inhibiting the thermal aggregation, considered by Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE), multiplies spectroscopy, and analysis of dynamic exchange of sulfhydryl-disulfide bonds. Meanwhile, the oxidation of exposed hydrophobic sites due to plasma treatment resulted in the transformation of the OVA molecule's surface from hydrophobic to hydrophilic, contributing significantly to the aggregation inhibition. Additionally, compared to an untreated sample of OVA, almost one-fold increase in emulsifying ability (EAI) and 1.5-fold in emulsifying stability (ESI) was observed after 4 min of plasma treatment. These findings demonstrated that plasma treatment not only enhanced the thermal stability of OVA, but also improved its emulsification properties.

Geriatric nutritional risk index predicts postoperative prognosis in older patients with hip fracture: A meta-analysis.

BACKGROUND: Hip fracture is common in elderly individuals and is accompanied by a relatively high mortality rate. However, it is currently difficult to accurately predict postoperative prognosis for older patients with hip fractures. The aim of this meta-analysis was to further determine the prognostic value of the geriatric nutritional risk index (GNRI) for patients who underwent hip fracture surgery. METHODS: The Medline, EMBASE, Web of Science, and CNKI databases were searched up to September 19, 2023, for available studies. The primary and secondary outcomes were the mortality and complication rates, respectively. Hazard ratios (HRs) and relative risks with corresponding 95% confidence intervals (CIs) were separately combined to assess the associations between the GNRI and mortality and complication rates. All the statistical analyses were performed with STATA 15.0 and SPSS 22.0 software. RESULTS: A total of 9 studies with 3959 patients were included. The pooled results demonstrated that a lower GNRI was significantly related to an increased risk of postoperative mortality (HR = 0.82, 95% CI = 0.72-0.92, P = .001). In addition, the GNRI predicted the risk of overall postoperative complications (52% vs 35.5%, P = .04) and pneumonia (33.3% vs 13.6%, P = .010). CONCLUSION: The GNRI might serve as a novel prognostic indicator for older patients with hip fractures, and a lower GNRI indicates an increased risk of postoperative mortality and complication rates.

Molecular Characteristics of JAK2 and Its Effect on the Milk Fat and Casein Synthesis of Ovine Mammary Epithelial Cells.

In addition to its association with milk protein synthesis via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, JAK2 also affects milk fat synthesis. However, to date, there have been no reports on the effect of JAK2 on ovine mammary epithelial cells (OMECs), which directly determine milk yield and milk contents. In this study, the coding sequence (CDS) region of ovine JAK2 was cloned and identified and its tissue expression and localization in ovine mammary glands, as well as its effects on the viability, proliferation, and milk fat and casein levels of OMECs, were also investigated. The CDS region of ovine JAK2, 3399 bp in length, was cloned and its authenticity was validated by analyzing its sequence similarity with JAK2 sequences from other animal species using a phylogenetic tree. JAK2 was found to be expressed in six ovine tissues, with the highest expression being in the mammary gland. Over-expressed JAK2 and three groups of JAK2 interference sequences were successfully transfected into OMECs identified by immunofluorescence staining. When compared with the negative control (NC) group, the viability of OMECs was increased by 90.1% in the pcDNA3.1-JAK2 group. The over-expression of JAK2 also increased the number and ratio of EdU-labeled positive OMECs, as well as the expression levels of three cell proliferation marker genes. These findings show that JAK2 promotes the viability and proliferation of OMECs. Meanwhile, the triglyceride content in the over-expressed JAK2 group was 2.9-fold higher than the controls and the expression levels of four milk fat synthesis marker genes were also increased. These results indicate that JAK2 promotes milk fat synthesis. Over-expressed JAK2 significantly up-regulated the expression levels of casein alpha s2 (CSN1S2), casein beta (CSN2), and casein kappa (CSN3) but down-regulated casein alpha s1 (CSN1S1) expression. In contrast, small interfered JAK2 had the opposite effect to JAK2 over-expression on the viability, proliferation, and milk fat and milk protein synthesis of OMECs. In summary, these results demonstrate that JAK2 promotes the viability, proliferation, and milk fat synthesis of OMECs in addition to regulating casein expression in these cells. This study contributes to a better comprehension of the role of JAK2 in the lactation performance of sheep.

The Causal Relationship between Plasma Myeloperoxidase Levels and Respiratory Tract Infections: A Bidirectional Mendelian Randomization Study.

Background: Observational researches reported the underlying correlation of plasma myeloperoxidase (MPO) concentration with respiratory tract infections (RTIs), but their causality remained unclear. Here, we examined the cause-effect relation between plasma MPO levels and RTIs. Materials and Methods: Datasets of plasma MPO levels were from the Folkersen et al. study (n = 21,758) and INTERVAL study (n = 3,301). Summarized data for upper respiratory tract infection (URTI) (2,795 cases and 483,689 controls) and lower respiratory tract infection (LRTI) in the intensive care unit (ICU) (585 cases and 430,780 controls) were from the UK Biobank database. The primary method for Mendelian randomization (MR) analysis was the inverse variance weighted approach, with MR-Egger and weighted median methods as supplements. Cochrane's Q test, MR-Egger intercept test, MR pleiotropy residual sum and outliers global test, funnel plots, and leave-one-out analysis were used for sensitivity analysis. Results: We found that plasma MPO levels were positively associated with URTI (odds ratio (OR) = 1.135; 95% confidence interval (CI) = 1.011-1.274; P=0.032) and LRTI (ICU) (OR = 1.323; 95% CI = 1.006-1.739; P=0.045). The consistent impact direction is shown when additional plasma MPO level genome-wide association study datasets are used (URTI: OR = 1.158; 95% CI = 1.072-1.251; P < 0.001; LRTI (ICU): OR = 1.216; 95% CI = 1.020-1.450; P=0.030). There was no evidence of a causal effect of URTI and LRTI (ICU) on plasma MPO concentration in the reverse analysis (P > 0.050). The sensitivity analysis revealed no violations of MR presumptions. Conclusions: Plasma MPO levels may causally affect the risks of URTI and LRTI (ICU). In contrast, the causal role of URTI and LRTI (ICU) on plasma MPO concentration was not supported in our MR analysis. Further studies are needed to identify the relationship between RTIs and plasma MPO levels.

Expression Localization of the KRT32 Gene and Its Association of Genetic Variation with Wool Traits.

Changes in keratin gene expression and spatiotemporal regulation determine the compositional content and cellular localization of wool keratin, thereby affecting wool traits. Therefore, keratin gene family member 32 (KRT32) was selected for a study using RT-qPCR, immunofluorescence, and penta-primer amplification refractory mutation system (PARMS) techniques. The results showed that KRT32 mRNA was highly expressed in the skin and localized to the inner root sheath (IRS), outer root sheath (ORS) and dermal papilla (DP). Sequencing results identified eight SNPs in KRT32, and association analyses revealed that the variations were significantly associated with multiple traits in wool (p < 0.05), including MFD, CF and MFC. The constructed haplotype combination H2H3 has higher CF and smaller MFD than other haplotype combination (p < 0.05). In conclusion, KRT32 can be used as a candidate gene for molecular genetic improvement of wool in Gansu Alpine Fine-wool sheep.

Association of Serum Uric Acid with Non-Valvular Atrial Fibrillation: A Retrospective Study in China.

Purpose: The association between serum uric acid (SUA) and atrial fibrillation (AF) has been widely focused on and studied in recent years. However, the exact association between SUA and AF is unclear, and the effect of gender on the association between SUA levels and AF has been controversial. This study aimed to investigate the association between SUA levels and non-valvular AF (NVAF) and the potential effect of gender on it. Patients and Methods: A total of 866 NVAF patients (463 males, age 69.44 ± 8.07 years) and 646 sex-matched control patients in sinus rhythm, with no history of arrhythmia were included in this study. t-test, ANOVA, and chi-square test were used for baseline data analysis. The receiver operating characteristic curve, logistic regression and Pearson correlation analysis were used for correlation analysis. Results: Compared to controls, NVAF patients exhibited higher SUA (P<0.001). After adjusting for confounders of NVAF, SUA remained significantly associated with NVAF, regardless of gender (OR= 1.31, 95% CI 1.18-1.43, P<0.001). SUA demonstrated higher predictability and sensitivity in predicting the occurrence of female NVAF compared to male (area under the curve was 0.68 (95% CI 0.64-0.72, P<0.001), sensitivity 87.3%), with the optimal cut-off point identified as 5.72 mg/dL. Furthermore, SUA levels correlated with APOA1, Scr and NT-proBNP in NVAF patients. SUA levels varied significantly among NVAF subtypes. Conclusion: High SUA levels were independently associated with NVAF, regardless of gender. SUA exhibited higher predictability and sensitivity in predicting the occurrence of NVAF in females compared to males. High SUA levels may affect other NVAF-related factors and participate in the pathophysiological process of NVAF.

[Effect of Zuogui Jiangtang Qinggan Formula on lipid metabolism in db/db mouse model of type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease].

This study aims to explore the effect of Zuogui Jiangtang Qinggan Formula(ZGJTQGF) on the lipid metabolism in the db/db mouse model of type 2 diabetes mellitus(T2DM) complicated with non-alcoholic fatty liver disease(NAFLD) via the insulin receptor(INSR)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/sterol-regulatory element-binding protein 2(SREBP-2) signaling pathway. Twenty-four db/db mice were randomized into positive drug(metformin, 0.067 g·kg~(-1)) and low-(7.5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) ZGJTQGF groups. Six C57 mice were used as the blank group and administrated with an equal volume of distilled water. The mice in other groups except the blank group were administrated with corresponding drugs by gavage for 6 consecutive weeks. At the end of drug administration, fasting blood glucose(FBG) and blood lipid levels were measured, and oral glucose tolerance test was performed. Compared with the blank group, the mice treated with ZGJTQGF showed decreased body mass and liver weight coefficient, lowered levels of FBG, total cholesterol(TC), triglyceride(TG), and low-density lipoprotein(LDL), and weakened liver function. The pathological changes and lipid accumulation in the liver tissue were examined. Western blot was employed to measure the protein levels of INSR, AMPK, p-AMPK, and SREBP-2. Compared with the blank group, the model group showed down-regulated protein levels of INSR and p-AMPK/AMPK and up-regulated protein level of SREBP-2. Compared with the model group, high-dose ZGJTQGF up-regulated the protein levels of INSR and p-AMPK/AMPK and down-regulated the protein level of SREBP-2. Low-dose ZGJTQGF slightly up-regulated the protein levels of INSR and p-AMPK/AMPK and down-regulated the protein level of SREBP-2, without significant differences. The results suggested that ZGJTQGF may alleviate insulin resistance and improve lipid metabolism in db/db mice by activating the INSR/AMPK/SREBP-2 signaling pathway.

TGF-ß1/SMAD3-driven GLI2 isoform expression contributes to aggressive phenotypes of hepatocellular carcinoma.

Hedgehog signaling is activated in response to liver injury, and modulates organogenesis. However, the role of non-canonical hedgehog activation via TGF-ß1/SMAD3 in hepatic carcinogenesis is poorly understood. TGF-ß1/SMAD3-mediated non-canonical activation was found in approximately half of GLI2-positive hepatocellular carcinoma (HCC), and two new GLI2 isoforms with transactivating activity were identified. Phospho-SMAD3 interacted with active GLI2 isoforms to transactivate downstream genes in modulation of stemness, epithelial-mesenchymal transition, chemo-resistance and metastasis in poorly-differentiated hepatoma cells. Non-canonical activation of hedgehog signaling was confirmed in a transgenic HBV-associated HCC mouse model. Inhibition of TGF-ß/SMAD3 signaling reduced lung metastasis in a mouse in situ hepatic xenograft model. In another cohort of 55 HCC patients, subjects with high GLI2 expression had a shorter disease-free survival than those with low expression. Moreover, co-positivity of GLI2 with SMAD3 was observed in 87.5% of relapsed HCC patients with high GLI2 expression, indicating an increased risk of post-resection recurrence of HCC. The findings underscore that suppressing the non-canonical hedgehog signaling pathway may confer a potential strategy in the treatment of HCC.

Radiogenomic analysis of ultrasound phenotypic features coupled to proteomes predicts metastatic risk in primary prostate cancer.

BACKGROUND: Primary prostate cancer with metastasis has a poor prognosis, so assessing its risk of metastasis is essential. METHODS: This study combined comprehensive ultrasound features with tissue proteomic analysis to obtain biomarkers and practical diagnostic image features that signify prostate cancer metastasis. RESULTS: In this study, 17 ultrasound image features of benign prostatic hyperplasia (BPH), primary prostate cancer without metastasis (PPCWOM), and primary prostate cancer with metastasis (PPCWM) were comprehensively analyzed and combined with the corresponding tissue proteome data to perform weighted gene co-expression network analysis (WGCNA), which resulted in two modules highly correlated with the ultrasound phenotype. We screened proteins with temporal expression trends based on the progression of the disease from BPH to PPCWOM and ultimately to PPCWM from two modules and obtained a protein that can promote prostate cancer metastasis. Subsequently, four ultrasound image features significantly associated with the metastatic biomarker HNRNPC (Heterogeneous nuclear ribonucleoprotein C) were identified by analyzing the correlation between the protein and ultrasound image features. The biomarker HNRNPC showed a significant difference in the five-year survival rate of prostate cancer patients (p < 0.0053). On the other hand, we validated the diagnostic efficiency of the four ultrasound image features in clinical data from 112 patients with PPCWOM and 150 patients with PPCWM, obtaining a combined diagnostic AUC of 0.904. In summary, using ultrasound imaging features for predicting whether prostate cancer is metastatic has many applications. CONCLUSION: The above study reveals noninvasive ultrasound image biomarkers and their underlying biological significance, which provide a basis for early diagnosis, treatment, and prognosis of primary prostate cancer with metastasis.

Screening and identification of lncRNAs in preadipocyte differentiation in sheep.

Studies of preadipocyte differentiation and fat deposition in sheep have mainly focused on functional genes, and with no emphasis placed on the role that long non-coding RNAs (lncRNAs) may have on the activity of those genes. Here, the expression profile of lncRNAs in ovine preadipocyte differentiation was investigated and the differentially expressed lncRNAs were screened on day 0 (D0), day 2(D2) and day 8(D8) of ovine preadipocyte differentiation, with their target genes being predicted. The competing endogenous RNA (ceRNA) regulatory network was constructed by GO and KEGG enrichment analysis for functional annotation, and some differentially expressed lncRNAs were randomly selected to verify the RNA-Seq results by RT-qPCR. In the study, a total of 2517 novel lncRNAs and 3943 known lncRNAs were identified from ovine preadipocytes at the three stages of differentiation, with the highest proportion being intergenic lncRNAs. A total of 3455 lncRNAs were expressed at all three stages of preadipocyte differentiation, while 214, 226 and 228 lncRNAs were uniquely expressed at day 0, day 2 and day 8, respectively. By comparing the expression of the lncRNAs between the three stages of differentiation stages, a total of 405, 272 and 359 differentially expressed lncRNAs were found in D0-vs-D2, D0-vs-D8, and D2-vs-D8, respectively. Functional analysis revealed that the differentially expressed lncRNAs were enriched in signaling pathways related to ovine preadipocyte differentiation, such as mitogen-activated protein kinase (MAPK) pathway, the phosphoinositide 3-kinase protein kinase B (PI3K-Akt) pathway, and the transforming growth factor beta (TGF-ß) pathway. In summary, lncRNAs from preadipocytes at different stages of differentiation in sheep were identified and screened using RNA-Seq technology, and the regulatory mechanisms of lncRNAs in preadipocyte differentiation and lipid deposition were explored. This study provides a theoretical reference for revealing the roles of lncRNAs in ovine preadipocyte differentiation and also offers a theoretical basis for further understanding the regulatory mechanisms of ovine preadipocyte differentiation.

Uptake and detection rate of colorectal cancer screening with colonoscopy in China: A population-based, prospective cohort study.

BACKGROUND: Colorectal cancer is the leading cause of cancer-related death worldwide. Colonoscopy is widely used as a screening test for detecting colorectal cancer in many countries. However, there is little evidence regarding the uptake and diagnostic yields of colonoscopy in population-based screening programs in countries with limited medical resources. OBJECTIVE: We reported the uptake of colonoscopy and the detection of colorectal lesions and explored related factors based on a colorectal cancer screening program in China. DESIGN: Individuals aged 45-74 years who were asymptomatic for colorectal cancer and had no history of colorectal cancer were recruited. An established risk score system was used to identify individuals at high risk for colorectal cancer, and they were subsequently recommended for colonoscopy. SETTING: A population-based, prospective cohort study was implemented in 169 communities, 14 districts of Chongqing, Southwest China. PARTICIPANTS: A total of 288,150 eligible participants were recruited from November 2013 to June 2021, and 41,315 participants were identified to be at high risk of colorectal cancer. METHODS: Generalized linear mixed model was used to explore the individual and community structural characteristics associated with uptake of colonoscopy. Additionally, the detection rate of colorectal lesions under colonoscopy screening was also reported, and their associated factors were explored. RESULTS: 7859 subjects underwent colonoscopy, with an uptake rate of 19.02 % (95 % CI 18.64 %-19.40 %). Lower uptake rates were associated with older age, lower education, more physical activity, and structural characteristics, including residing in developing areas (OR 0.73, 95 % CI 0.69-0.78), residing more than 5 km from screening hospital (5-10 km: OR 0.85, 95 % CI 0.79-0.91; >10 km: OR 0.85, 95 % CI 0.80-0.91), and not being exposed to social media publicity (OR 0.63, 95 % CI 0.53-0.75). Overall, 8 colorectal cancers (0.10 %), 423 advanced adenomas (5.38 %), 820 nonadvanced adenomas (10.43 %), and 684 hyperplastic polyps (8.70 %) were detected, with an adenoma detection rate of 15.92 %. Several factors, including older age, male, current smoking and a family history of colorectal cancer, were positively related to colorectal neoplasms. CONCLUSIONS: The uptake of colonoscopy for colorectal cancer screening was not optimal among a socioeconomically diverse high-risk population. The screening strategy should attempt to ensure equitable access to screening according to regional characteristics, and enhance the uptake of colonoscopy by recommended multifaceted interventions, which focus on individuals with poor compliance, select a closer screening hospital, and strengthen social media publicity at the structural level.