FXR1 facilitates axitinib resistance in clear cell renal cell carcinoma via regulating KEAP1/Nrf2 signaling pathway.

Axitinib is emerging as a first-line combination treatment drug for metastatic renal cell carcinoma, but the acquired resistance significantly bothers the treatment efficacy. This article is to investigate the impact of fragile X mental retardation autosomal homolog 1 (FXR1) and its mechanistic involvement with Kelch-like epoxy chloropropan-associated protein 1 (KEAP1)/NF-E2-related factor 2 (Nrf2) pathway on cell resistance to axitinib in clear cell renal cell carcinoma (ccRCC). Establishment of axitinib resistance cells (786-O, Caki-1, 786-O/axitinib, or Caki-1/axitinib) was made, and the cells were then transfected with sh-FXR1, or co-transfected with sh-FXR1 and sh-KEAP1. The quantitative real-time PCR (qRT-PCR) and western blotting assays were employed to measure the expression of FXR1, KEAP1, Nrf2, LC3 II/I, Beclin 1, p62, MDR-1, and MRP-1. In addition, the binding between FXR1 and KEAP1 was verified by RNA-immunoprecipitation and RNA pull-down assays, and FXR1-dependent KEAP1 mRNA degradation was determined. Herein, FXR1 was demonstrated to be overexpressed in ccRCC cells, and showed higher expression in 786-O/axitinib and Caki-1/axitinib cells. Mechanistically, FXR1 enriched KEAP1 mRNA, and pulled downed by biotinylated KEAP1 probes. Results of RNA stability assay reveled that KEAP mRNA stability was suppressed by FXR1. Furthermore, knockdown of FXR1 promoted cell apoptosis and showed a restrained feature on cell resistance to axitinib. Of note, KEAP1 knockdown suppressed cell autophagy, oxidative stress, resistance to axitinib, and promoted apoptosis, despite FXR1 was downregulated in ccRCC cells. In conclusion, FXR1 played an encouraging role in ccRCC cell resistance to axitinib by modulating KEAP/Nrf2 pathway.

Design, synthesis, and analgesia evaluation of novel Transient Receptor Potential Vanilloid 1 (TRPV1) agonists modified from Cannabidiol (CBD).

Pain-relief is a long-term research hotspot with huge demand in clinical treatment. The analgesics currently used have several side effects, such as being addictive and causing gastrointestinal bleeding. Therefore, new drugs and targets in analgesic field are both desirable. Transient Receptor Potential Vanilloid 1 (TRPV1) plays an essential role in pain perception and regulation, providing a new strategy for the development of antinociceptive agents. Here, a series of novel TRPV1 agonists were designed and synthesized based on Cannabidiol (CBD), a widely used pain-relieving agent with weak agonistic activity on TRPV1. According to the results of systematic in vitro and in vivo biological assays, compound 10f was finally identified as a promising TRPV1 agonist, with higher target affinity, stronger analgesic activity, and weak side effect of hyperthermia. Molecular docking simulations revealed a significant hydrogen bond interaction between 10f and Arg557, an amino acid residue key to the activity of TRPV1 protein. Taken together, compound 10f can be used as a lead compound for further optimization.

6-Shogaol as a Novel Thioredoxin Reductase Inhibitor Induces Oxidative-Stress-Mediated Apoptosis in HeLa Cells.

Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs. 6-Shogaol (6-S), a primary bioactive compound in ginger, has high anticancer activity. However, its potential mechanism of action has not been thoroughly investigated. In this study, we demonstrated for the first time that 6-S, a novel TrxR inhibitor, promoted oxidative-stress-mediated apoptosis in HeLa cells. The other two constituents of ginger, 6-gingerol (6-G) and 6-dehydrogingerduone (6-DG), have a similar structure to 6-S but fail to kill HeLa cells at low concentrations. 6-Shogaol specifically inhibits purified TrxR1 activity by targeting selenocysteine residues. It also induced apoptosis and was more cytotoxic to HeLa cells than normal cells. The molecular mechanism of 6-S-mediated apoptosis involves TrxR inhibition, followed by an outburst of reactive oxygen species (ROS) production. Furthermore, TrxR knockdown enhanced the cytotoxic sensitivity of 6-S cells, highlighting the physiological significance of targeting TrxR by 6-S. Our findings show that targeting TrxR by 6-S reveals a new mechanism underlying the biological activity of 6-S and provides meaningful insights into its action in cancer therapeutics.

Eltrombopag Inhibits Metastasis in Breast Carcinoma by Targeting HuR Protein.

Eltrombopag is a small molecule TPO-R agonist that has been shown in our previous studies to inhibit tumor growth by targeting Human antigen R (HuR) protein. HuR protein not only regulates the mRNA stability of tumor growth-related genes, but it also regulates the mRNA stability of a variety of cancer metastasis-related genes, such as Snail, Cox-2, and Vegf-c. However, the role and mechanisms of eltrombopag in breast cancer metastasis have not been fully investigated. The purpose of this study was to investigate whether eltrombopag can inhibit breast cancer metastasis by targeting HuR. Our study first found that eltrombopag can destroy HuR-AU-rich element (ARE) complexes at the molecular level. Secondly, eltrombopag was found to suppress 4T1 cell migration and invasion and inhibit macrophage-mediated lymphangiogenesis at the cellular level. In addition, eltrombopag exerted inhibitory effects on lung and lymph node metastasis in animal tumor metastasis models. Finally, it was verified that eltrombopag inhibited the expressions of Snail, Cox-2, and Vegf-c in 4T1 cells and Vegf-c in RAW264.7 cells by targeting HuR. In conclusion, eltrombopag displayed antimetastatic activity in breast cancer in an HuR dependent manner, which may provide a novel application for eltrombopag, hinting at the multiple effects of HuR inhibitors in cancer therapy.

Pseudoephedrine and its derivatives antagonize wild and mutated severe acute respiratory syndrome-CoV-2 viruses through blocking virus invasion and antiinflammatory effect.

The coronavirus disease 2019 has infected over 150 million people worldwide and led to over 3 million deaths. Severe acute respiratory syndrome (SARS)-CoV-2 lineages B.1.1.7, B.1.617, B.1.351, and P.1 were reported to have higher infection rates than that of wild one. These mutations were noticed to happen in the receptor-binding domain of spike protein (S-RBD), especially mutations N501Y, E484Q, E484K, K417N, K417T, and L452R. Currently, there is still no specific medicine against the virus; moreover, cytokine storm is also a dangerous factor for severe infected patients. In this study, potential S-RBD-targeted active monomers from traditional Chinese medicine Ephedra sinica Stapf (ephedra) were discovered by virtual screening. NanoBiT assay was performed to confirm blocking activities of the screened compounds against the interaction between SARS-CoV-2 S-RBD and angiotensin-converting enzyme 2 (ACE2). We further analyzed the blocking effect of the active compounds on the interactions of mutated S-RBD and ACE2 by computational studies. Moreover, antiinflammatory activities were evaluated using qRT-PCR, enzyme-linked immune sorbent assay, and Western blot analysis. As a result, pseudoephedrine (MHJ-17) and its derivative (MHJ-11) were found as efficient inhibitors disrupting the interactions between ACE2 and both wild and mutated S-RBDs. In addition, they also have antiinflammatory activities, which can be potential drug candidates or lead compounds for further study.

Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis.

RATIONALE: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. METHODS: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. MEASUREMENTS AND MAIN RESULTS: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. CONCLUSIONS: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.

Z-ligustilide provides a neuroprotective effect by regulating the phenotypic polarization of microglia via activating Nrf2-TrxR axis in the Parkinson's disease mouse model.

The polarization phenotype of microglia is critical in the progression of Parkinson's disease (PD). Molecules that can polarize microglia toward the M2 phenotype represent a promising class of compounds for anti-PD medications. Z-ligustilide (ZLG) is a naturally occurring enol ester with diverse pharmacological properties, especially in neuroprotection. For the first time, we investigated the effect of ZLG on anti-PD and elucidated its underlying mechanism. The results primarily showed that ZLG attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra. Mechanistically, ZLG alleviates oxidative stress-induced apoptosis of microglia by triggering the endogenous antioxidant system. Besides, ZLG modulated phenotypic polarization of the microglia through the activation of the Nrf2-TrxR axis, leading to microglia polarization towards the M2 phenotype. Taken together, our research showed that ZLG is a prospective therapy candidate for PD by altering microglia polarization and restoring redox equilibrium through the Nrf2-TrxR axis.

Upregulated PPP1R14B is connected to cancer progression and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) is an oncogenic gene found in a variety of tumors, but its role in the prognosis and development of kidney renal clear cell carcinoma (KIRC) remains unknown. Our study aimed to determine whether PPP1R14B could be a prognostic biomarker for KIRC and its role in the development of KIRC. METHODS: In this work, we used The Cancer Genome Atlas (TCGA) database to explore the expression of PPP1R14B in tumor tissues, its relationship with the prognosis of tumor patients, and its role in tumor occurrence and development. We validated our findings using the International Cancer Genome Consortium (ICGC) cohort, our clinical samples, and in vitro experiments. RESULTS: PPP1R14B was upregulated in KIRC compared to adjacent normal tissue. Moreover, multivariate analysis revealed that upregulated PPP1R14B expression was an independent risk factor for KIRC progression. High-PPP1R14B groups had shorter overall survival (OS) and disease-free survival (DFS) in TCGA and ICGC cohorts. We used Cell Counting Kit-8 (CCK8) and scratch wound healing assay to explore the proliferation and migration of KIRC cells following PPP1R14B knockdown. Our results indicated that PPP1R14B knockdown significantly reduced the proliferation and migration of KIRC cells in vitro. We also explored the possible cellular mechanisms of PPP1R14B through the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) analysis, and TISIDB analysis. The function enrich analysis revealed that PPP1R14B-related genes were mainly enriched in purine metabolism and the macromolecule catabolic process. PPP1R14B expression was associated with tumor-infiltrating immune cells (TIICs) in the TCGA cohort, and the results of single-cell RNA-seq (scRNA) further demonstrated that PPP1R14B expression was associated with the enhanced infiltration of CD8 + T lymphocytes. CONCLUSION: PPP1R14B may serve as a prognostic biomarker in KIRC, affect purine metabolism, activate immune infiltration, and promote KIRC cell migration.

Salidroside derivative SHPL-49 attenuates glutamate excitotoxicity in acute ischemic stroke via promoting NR2A-CAMKâ ¡α-Akt /CREB pathway.

BACKGROUND: Ischemic stroke is a significant cause of death and disability with a limited treatment time window. The reduction of early glutamate excitotoxicity using neuroprotective agents targeting N-methyl-d-aspartic acid (NMDA) receptors have attracted recent research attention. SHPL-49, a structurally modified derivative of salidroside, was synthesized by our team. Previous studies have confirmed the neuroprotective efficacy of SHPL-49 in rats with ischemic stroke. However, the underlying mechanisms need to be clarified. METHODS: We conducted in vivo experiments using the permanent middle cerebral artery occlusion rat model to investigate the role of SHPL-49 in glutamate release at different time points and treatment durations. Glutamate transporters and receptor proteins and neural survival proteins in the brain were also examined at the same time points. In vitro, primary neurons and the coculture system of primary neurons-astrocytes were subjected to oxygen-glucose deprivation and glutamate injury. Proteomics and parallel reaction monitoring analyses were performed to identify potential therapeutic targets of SHPL-49, which were further confirmed through in vitro experiments on the inhibition and mutation of the target. RESULTS: SHPL-49 significantly reduced glutamate release caused by hypoxia-ischemia. One therapeutic pathway of SHPL-49 was promoting the expression of glutamate transporter-1 to increase glutamate reuptake and further reduce the occurrence of subsequent neurotoxicity. In addition, we explored the therapeutic targets of SHPL-49 and its regulatory effects on glutamate receptors for the first time. SHPL-49 enhanced neuroprotection by activating the NMDA subunit NR2A, which upregulated the cyclic-AMP response binding protein (CREB) neural survival pathway and Akt phosphorylation. Since calcium/calmodulin-dependent kinase IIα (CaMKIIα) is necessary for synaptic transmission of NMDA receptors, we explored the interaction between CaMKIIα and SHPL-49, which protected CaMKIIα from hypoxia-ischemia-induced autophosphorylation damage. CONCLUSION: Overall, SHPL-49 enhanced neuronal survival and attenuated acute ischemic stroke by promoting the NR2A-CAMKⅡα-Akt/CREB pathway. Our study provides the first evidence demonstrating that the neuroprotective effect of SHPL-49 is achieved by promoting the NR2A subunit to extend the treatment time window, making it a promising drug for ischemic stroke.

Juglone suppresses vasculogenic mimicry in glioma through inhibition of HuR-mediated VEGF-A expression.

Vasculogenic mimicry (VM) serves as a vascular-like channel that provides important substances for tumor growth and is a primary factor in glioblastoma (GBM) drug resistance. Human Antigen R (HuR)-an mRNA-binding protein-is highly expressed in GBM, closely related to tumor progression, and deemed a potential drug target. Although some small-molecule compounds have been identified to disrupt HuR binding to target mRNA, they remain in the preclinical research stage, suggesting the need for further validation and development of HuR inhibitors. In our study, we aim to screen for potential HuR inhibitors and investigate their efficacy and molecular mechanisms in GBM. We employed the fluorescence polarization method to identify HuR inhibitors from a natural compound library, confirming the efficacy of juglone in effectively inhibiting the binding of HuR to AREVegf-a. Further validation of the binding of juglone to HuR at the protein level was conducted through electrophoretic mobility shift analysis, surface plasmon resonance, and molecular docking. Furthermore, juglone demonstrated inhibitory effects on glioma growth and VM formation in vitro and in vivo. Moreover, it was observed that juglone reversed epithelial-mesenchymal transition by inhibiting the VEGF-A/VEGFR2/AKT/SNAIL signaling pathway. Finally, we established the capability of juglone to target HuR in U251 cells through HuR knockdown, mRNA stability, and cell thermal shift assays. Therefore, this study identifies juglone as a novel HuR inhibitor, potentially offering promise as a lead compound for anti-VM therapy in GBM by targeting HuR. Abbreviations: AKT, protein kinase B; ARE, adenine-and uridine-rich elements; CETSA, cellular thermal shift assay; DMEM, Dulbecco's modified Eagle's medium; ELISA, enzyme linked immune sorbent assay; EMSA, electrophoretic mobility shift assay; EMT, epithelial mesenchymal transition; FP, fluorescence polarization; GBM, glioblastoma; HTS, high-throughput screening; HuR, human antigen R; IF, Immunofluorescence; PAS, periodic acid-Schiff; PI3K, phosphoinositide-3 kinase; qRT-PCR, quantitative real-time PCR; RRMs, RNA recognition motifs; SPR, surface plasmon resonance. TMZ, temozolomide; VM, vasculogenic mimicry; VEGF-A, Vascular endothelial growth factor-A; VEGFR2, Vascular endothelial growth factor receptor-2.

Systematic overview of intraosseous access versus intravenous delivery for emergency resuscitation: Efficacy and quality of existing evidence.

BACKGROUND: The impact of intraosseous (IO) access on resuscitation outcomes, as compared to intravenous (IV) administration, is subject to ongoing debate. This review aims to provide a comprehensive evaluation of the methodological, reporting, and evidence quality of existing Systematic Reviews/Meta-Analyses (SRs/MAs) on IO use during resuscitation. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a strategic literature search to identify pertinent SRs/MAs published up until May 6th, 2023. After an extensive screening process, 4 SRs/MAs were included for review. We used the A Measurement Tool to Assess Systematic Reviews-2 tool for assessing methodological quality, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist for evaluating reporting quality, and the Grading of Recommendations Assessment, Development, and Evaluation framework for examining the quality of evidence. RESULTS: The assessment revealed high methodological quality across all the included SRs/MAs but showed significant variability in the quality of evidence. The studies offered conflicting findings on the impact of IO access on resuscitation outcomes such as return of spontaneous circulation, survival rates at hospital discharge, and favorable neurological outcomes. Some studies suggested an association of IO access with poorer outcomes, while others indicated no significant difference between IO and IV routes. CONCLUSIONS: Despite the perceived utility of IO access when IV access is unachievable, the impact of IO on survival, return of spontaneous circulation, and neurological outcomes remains ambiguous due to the inconsistency in the existing evidence. This review underscores the critical need for more rigorous and consistent primary research in this area to strengthen clinical guidelines and improve patient outcomes.

Neuroprotective effects of the salidroside derivative SHPL-49 via the BDNF/TrkB/Gap43 pathway in rats with cerebral ischemia.

Ischemic stroke is a common intravascular disease and one of the leading causes of death and disability. The salidroside derivative SHPL-49, which we previously synthesized, significantly attenuates cerebral ischemic injury in a rat model of permanent middle cerebral artery occlusion. To explore the neuroprotective mechanism of SHPL-49, the effects of SHPL-49 on the expression levels of neurotrophic factors in neurons and microglia and the polarization of microglia were investigated in the present study. SHPL-49 activated the brain-derived neurotrophic factor (BDNF) pathway, decreased the number of degenerated neurons, and accelerated neurogenesis in rats with cerebral ischemia. In addition, SHPL-49 promoted the polarization of microglia toward the M2 phenotype to alleviate neuroinflammation. In BV2 cells, SHPL-49 upregulated CD206 mRNA and protein levels and inhibited CD86 mRNA and protein levels. SHPL-49 also increased neurotrophic factor secretion in BV2 cells, which indirectly promoted the survival of primary neurons after oxygen-glucose deprivation (OGD). Proteomics analysis revealed that SHPL-49 promoted growth-associated protein 43 (Gap43) expression. SHPL-49 enhanced synaptic plasticity and increased Gap43 protein levels via activation of the BDNF pathway in the OGD primary neuron model. These results indicate that SHPL-49 prevents cerebral ischemic injury by activating neurotrophic factor pathways and altering microglial polarization. Thus, SHPL-49 is a potential neuroprotective agent.

Comprehensive analysis of vulnerability status and associated affect factors among prehospital emergency patients: a single-center descriptive cross-sectional study.

Background: Prehospital emergency care is a critical but often understudied aspect of healthcare. Patient vulnerability in this setting can significantly impact outcomes. The aim of this study was to investigate the vulnerability status and to determine associated affect factors among prehospital emergency patients in China. Methods: In this cross-sectional study conducted in China, from April 2023 to July 2023, we assessed the vulnerability of prehospital emergency patients using the Safety in Prehospital Emergency Care Index (SPECI) scale. We conducted a detailed questionnaire-based survey to gather demographic and disease-related information. We employed the SPECI scale, consisting of two subscales, to evaluate patient vulnerability. Statistical analyses, including t-tests, ANOVA, and multiple linear regression, were used to identify factors associated with vulnerability. Results: The study included a total of 973 prehospital emergency patients, with a response rate of 81.9%. These patients exhibited a low-to-moderate level of vulnerability, with an average SPECI score of 14.46 out of 40. Vulnerability was significantly associated with age (particularly those aged 60 and above), disease severity (severe conditions increased vulnerability), disease type (circulatory diseases correlated with higher vulnerability), alterations in consciousness, and chronic diseases. Unexpectedly, digestive system diseases were negatively correlated with vulnerability. Conclusion: Addressing patient vulnerability in prehospital care is essential. Tailored interventions, EMS provider training, and interdisciplinary collaboration can mitigate vulnerability, especially in older patients and those with severe conditions.

Single cell RNA-Sequencing Reveals Mast Cells Enhance Mononuclear Phagocytes Infiltration in Bladder Cancer Microenvironment.

Objective: Investigating the interaction between Mast cells (MCs) and Mononuclear Phagocytes (MPs) in the tumor microenvironment (TME) of blader cancer (BCa) to uncover potential immunotherapeutic targets. Methods: Single-cell RNA sequencing (scRNA-Seq) was conducted on 12 BCa patients to identify distinct subgroups of MCs and MPs. Transcriptome data was analyzed to characterize the phenotype, gene enrichment, cell-cell communication, and biological processes. The expression levels of cytokines were assessed by enzyme-linked immunosorbent assay (ELISA), while the chemotactic effects of cytokines were evaluated through Transwell assay. Results: In muscle-invasive bladder cancer (MIBC), the proportion of interferon-stimulated MC subtype (Mast-ISG15) increased. Mast-IL13 subgroup and Mast-CCL2 subgroups were functionally enriched in interferon (IFN) and nuclear factor kappa-B (NF-κB) signaling pathways. The Mast-CCL2 subgroup overexpressed the CCL2 gene, which could chemoattract MPs through CCL2. In vitro experiments confirmed that under stimulation, activated MCs activated IFN and NF-κB signaling, increasing the secretion of CCL2 and IL-13, chemoattracted THP-1 monocyte. Conclusion: This study revealed the vital role of MCs in shaping the TME of BCa. And provides new insights for the precise treatment of BCa.

Prognostic analysis of anoikis-related genes in bladder cancer: An observational study.

Anoikis is proved to play a crucial role in the development of cancers. However, the impact of anoikis on the prognosis of bladder cancer (BLCA) is currently unknown. Thus, this study aimed to find potential effect of anoikis in BLCA. The Cancer Genome Atlas (TCGA)-BLCA and GSE13507 cohorts were downloaded from TCGA and the Gene Expression Omnibus (GEO) databases, respectively. Differentially expressed genes (DEGs) were screened between BLCA and normal groups, which intersected with anoikis-related genes to yield anoikis-related DEGs (AR DEGs). Univariate COX, rbsurv, and multivariate COX analyses were adopted in order to build a prognostic risk model. The differences of risk score in the different clinical subgroups and the relevance between survival rate and clinical characteristics were explored as well. Finally, chemotherapy drug sensitivity in different risk groups was analyzed. In total, 78 AR DEGs were acquired and a prognostic signature was build based on the 6 characteristic genes (CALR, FASN, CSPG4, HGF, INHBB, SATB1), where the patients of low-risk group had longer survival time. The survival rate of BLCA patients was significantly differential in different groups of age, stage, smoking history, pathologic-T, and pathologic-N. The IC50 of 56 drugs showed significant differences between 2 risk groups, such as imatinib, docetaxel, and dasatinib. At last, the results of real time quantitative-polymerase chain reaction (RT-qPCR) demonstrated that the expression trend of CALR, HGF, and INHBB was consistent with the result obtained previously based on public databases. Taken together, this study identified 6 anoikis-related characteristic genes (CALR, FASN, CSPG4, HGF, INHBB, SATB1) for the prognosis of BLCA patients, providing a scientific reference for further research on BLCA.

Association Between Age at Diabetes Diagnosis and Subsequent Incidence of Cancer: A Longitudinal Population-Based Cohort.

OBJECTIVE: Diabetes presenting at a younger age has a more aggressive nature. We aimed to explore the association of age at type 2 diabetes mellitus (T2DM) diagnosis with subsequent cancer incidence in a large Chinese population. RESEARCH DESIGN AND METHODS: The prospective population-based longitudinal cohort included 428,568 newly diagnosed T2DM patients from 2011 to 2018. Participants were divided into six groups according to their age at diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years. The incidence of overall and 14 site-specific cancers was compared with the Shanghai general population including 100,649,346 person-years. RESULTS: A total of 18,853 and 582,643 overall cancer cases were recorded in the T2DM cohort and the general population. The age-standardized rate of overall cancer in T2DM patients was 501 (95% CI: 491, 511) per 100,000 person-years, and the standardized incidence ratio (SIR) was 1.10 (1.09, 1.12). Younger age at T2DM diagnosis was associated with higher incidence of overall and site-specific cancers. SIRs for overall cancer with T2DM diagnosis at ages 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years were 1.48 (1.41, 1.54), 1.30 (1.25, 1.35), 1.19 (1.15, 1.23), 1.16 (1.12, 1.20), 1.06 (1.02, 1.10), and 0.86 (0.84, 0.89), respectively. Similar trends were observed for site-specific cancers, including respiratory, colorectum, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancer and lymphoma among both males and females. CONCLUSIONS: Our findings highlight the necessity of stratifying management for T2DM according to age of diagnosis. As with a range of vascular outcomes, age-standardized cancer risks are greater in earlier compared with later onset T2DM.

Macrophage ß2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis.

HuR is a member of the Drosophila Elav protein family that binds mRNA degradation sequences and prevents RNase-mediated degradation. Such HuR-mediated mRNA stabilization, which is stimulated by integrin engagement and is controlled at the level of HuR nuclear export, is critically involved in T-cell cytokine production. However, HuR's role in macrophage soluble factor production, in particular in response to angiogenic stimuli, has not yet been established. We show that the labile transcripts that encode vascular endothelial growth factor and matrix metalloproteinase-9 are stabilized when murine macrophages adhere to the ß(2) integrin ligand intercellular adhesion molecule-1. This mRNA stabilization response was absent in bone marrow-derived macrophages obtained from conditional macrophage-specific HuR knockout mice. The microvascular angiogenic response to an inflammatory stimulus (ie, subcutaneous polyvinyl alcohol sponge implantation) was markedly diminished in these macrophage HuR knockout mice despite the equal levels of macrophage localization to those observed in littermate wild-type controls. Furthermore, blood flow recovery and ischemic muscle neovascularization after femoral artery ligation were impaired in the conditional macrophage-specific HuR knockout mice. These results demonstrate that dynamic effects on mRNA, mediated by the RNA-binding and RNA-stabilizing protein HuR, are required for macrophage production of angiogenic factors, which play critical roles in the neovascular responses to a variety of stimuli, including tissue ischemia.

Both total testosterone and sex hormone-binding globulin are independent risk factors for metabolic syndrome: results from Fangchenggang Area Male Health and Examination Survey in China.

BACKGROUND: Metabolic syndrome is often beneficial from testosterone replacement therapy. Although testosterone and sex hormone-binding globulin (SHBG) are inversely associated with the risk of metabolic syndrome, it is controversial whether the association between testosterone and metabolic syndrome is independent of SHBG. METHODS: Testosterone, SHBG and metabolic syndrome were evaluated in 2361 men aged 20-73 years, who participated in the population-based Fangchenggang Area Male Health and Examination Survey. Total testosterone, SHBG and other biochemical profiles were measured. Free testosterone and bioavailable testosterone were calculated on the basis of Vermeulen's formula. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria for Asian population. The independent associations with metabolic syndrome were determined by multivariate logistic regression analysis. RESULTS: Men with metabolic syndrome had a lower level of total testosterone, bioavailable testosterone, free testosterone, or SHBG than those without metabolic syndrome (all p < 0.001). Both total testosterone and SHBG were inversely correlated with body mass index or homeostasis model assessment of insulin resistance (all age-adjusted p < 0.001). Men within the lowest quartile of total testosterone [odds ratio (OR) = 4.86, 95% confidence interval (CI) = 2.72-8.68], bioavailable testosterone (OR = 3.04, 95% CI = 1.81-5.10), free testosterone (OR = 3.08, 95% CI = 1.81-5.27) or SHBG (OR = 4.28, 95% CI = 2.52-7.27) had a risk of metabolic syndrome after adjusting for age, smoking, homeostasis model assessment of insulin resistance and body mass index. Total testosterone remained inversely associated with metabolic syndrome after further adjusting for SHBG (OR = 0.95, 95% CI = 0.92-0.99), while SHBG remained inversely associated with metabolic syndrome after further adjusting for total testosterone (OR = 0.99, 95% CI = 0.97-1.00). CONCLUSION: Total testosterone and SHBG are independent risk factors of metabolic syndrome. Prospective studies are needed to explore whether the association between sex hormones and metabolic syndrome was mediated by insulin resistance or obesity.

Comprehensive assessment of emergency departments in county-level public hospitals: a multicenter descriptive cross-sectional study in Henan province, China.

Background: Emergency Departments (EDs) play a crucial role in providing immediate medical care, particularly in densely populated countries like China. While previous research has predominantly focused on well-funded urban hospitals, this study offers a comprehensive evaluation of EDs in county-level public hospitals in Henan province, China, aiming to identify disparities and challenges. Methods: A descriptive cross-sectional survey was conducted in 382 public hospitals across Henan province, China, from July 1, 2023, to August 1, 2023. Data were collected using an electronic questionnaire covering hospital information, human resources, infrastructure, clinical capabilities, and operational capacities. The data collection period for this survey spanned from January 1 to December 31, 2022. Results: With a remarkable 94.0% response rate, our study reveals significant disparities in county-level public hospitals compared to their provincial or municipal counterparts in Henan Province, China. County-level hospitals, which constitute 266 of the total 342 surveyed facilities, exhibit notable differences, including fewer doctors (median: 11 vs. 23, p < 0.0001) and nurses (median: 18 vs. 37, p < 0.0001). Additionally, a higher proportion of junior doctors is observed in these hospitals, while senior medical staff are more prevalent in provincial or municipal hospitals (p < 0.001). County-level hospitals also face resource challenges, with fewer beds in the emergency room (median: 4 vs. 7, p = 0.0003) and limited proficiency in advanced clinical procedures such as POCT, fiberoptic bronchoscopy, CRRT, ECMO, ultrasound equipment operation, and intraosseous infusion, with significant differences noted in most of these capabilities (p < 0.05). Operational capabilities show distinctions as well, with county-level hospitals managing a lower patient volume (median: 14,516 vs. 34,703, p < 0.0001) and handling fewer pre-hospital CPR cases (median: 33 vs. 89, p < 0.0001). In-hospital CPR success rates are also lower in county-level hospitals (median ROSC: 25.0% vs. 42.8%, p = 0.0068). Conclusion: While provincial or municipal hospitals enjoy better resources, county-level hospitals, especially crucial in less urbanized regions, face substantial challenges. Addressing these disparities is imperative, necessitating targeted investments, improved infrastructure, enhanced clinical training, and the adoption of innovations like telemedicine to enhance the quality of emergency care.

An inductive knowledge graph embedding via combination of subgraph and type information.

Conventional knowledge graph representation learn the representation of entities and relations by projecting triples in the knowledge graph to a continuous vector space. The vector representation increases the precision of link prediction and the efficiency of downstream tasks. However, these methods cannot process previously unseen entities during the knowledge graph evolution. In other words, the model trained on the source knowledge graph cannot be applied to the target knowledge graph containing new unseen entities. Recently, a few subgraph-based link prediction models obtained the inductive ability, but they all neglect semantic information. In this work, we propose an inductive representation learning model TGraiL which considers not only the topological structure but also semantic information. First, distance in the subgraph is used to encode the node's topological structure. Second, the projection matrix is used to encode the entity type information. Finally, both kinds of information are fused for training to acquire the ultimate vector representation of entities. The experimental results indicate that the model's performance has been significantly improved compared to the existing baseline models, demonstrating the method's effectiveness and superiority.