A nomogram clinical prediction model for predicting urinary infection stones: development and validation in a retrospective study.

PURPOSE: This study aimed to develop a nomogram prediction model to predict the exact probability of urinary infection stones before surgery in order to better deal with the clinical problems caused by infection stones and take effective treatment measures. METHODS: We retrospectively collected the clinical data of 390 patients who were diagnosed with urinary calculi by imaging examination and underwent postoperative stone analysis between August 2018 and August 2023. The patients were randomly divided into training group (n = 312) and validation group (n = 78) using the "caret" R package. The clinical data of the patients were evaluated. Univariate and multivariate logistic regression analysis were used to screen out the independent influencing factors and construct a nomogram prediction model. The receiver operating characteristic curve (ROC), calibration curves, and decision curve analysis (DCA) and clinical impact curves were used to evaluate the discrimination, accuracy, and clinical application efficacy of the prediction model. RESULTS: Gender, recurrence stones, blood uric acid value, urine pH, and urine bacterial culture (P < 0.05) were independent predictors of infection stones, and a nomogram prediction model ( https://zhaoyshenjh.shinyapps.io/DynNomInfectionStone/ ) was constructed using these five parameters. The area under the ROC curve of the training group was 0.901, 95% confidence interval (CI) (0.865-0.936), and the area under the ROC curve of the validation group was 0.960, 95% CI (0.921-0.998). The results of the calibration curve for the training group showed a mean absolute error of 0.015 and the Hosmer-Lemeshow test P > 0.05. DCA and clinical impact curves showed that when the threshold probability value of the model was between 0.01 and 0.85, it had the maximum net clinical benefit. CONCLUSIONS: The nomogram developed in this study has good clinical predictive value and clinical application efficiency can help with risk assessment and decision-making for infection stones in diagnosing and treating urolithiasis.

Association between multiple sleep dimensions in obstructive sleep apnea and the early sign of atherosclerosis.

STUDY OBJECTIVES: We investigated the associations between multiple sleep dimensions in obstructive sleep apnea (OSA) and carotid intima-media thickness (CIMT), an early sign of atherosclerosis, in subjects from the Shanghai Sleep Health Study (SSHS). METHODS: We performed secondary analysis of SSHS in a group of subjects performed the ultrasound evaluation from 2018 to 2022. Multiple sleep dimensions were measured using standard polysomnography. CIMT was measured from ultrasound images as an early sign of atherosclerosis. Multivariable-adjusted linear regression and logistic regression analyses were performed to detect associations between sleep traits in OSA and CIMT. RESULTS: CIMT was found to increase with increasing severity of OSA (P < 0.001). When adjusted for conventional risk factors, microarousal index (MAI) and hypoxic burden (HB) were positively correlated with CIMT while slow wave sleep (SWS) and mean apnea-hypopnea event duration (MAHD) showed negative correlation with CIMT (all P < 0.01). In binary logistic regression analysis, participants with high MAI, less SWS, higher HB and shorter MAHD showed a higher prevalence of thick CIMT with no evidence of interaction by age, sex, or body mass index (P-interaction > 0.05). CONCLUSIONS: Subjects with more severe sleep fragmentation, more severe hypoxemia and increased arousability were more likely to have increased CIMT after adjusting for potential confounders. It is important to evaluate novel indices of sleep fragmentation, hypoxemia and arousability in OSA for early detection and prevention of cardiovascular disease, including stroke. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry; URL: http://www.chictr.org.cn/showproj.aspx?proj=43057; No. ChiCTR1900025714.

Tumor Necrosis Factor Receptor-Associated Factor 6 and Human Cancer: A Systematic Review of Mechanistic Insights, Functional Roles, and Therapeutic Potential.

Cancer imposes a substantial burden and its incidence is persistently increasing in recent years. Cancer treatment has been difficult due to its inherently complex nature. The tumor microenvironment (TME) includes a complex interplay of cellular and noncellular constituents surrounding neoplastic cells, intricately contributing to the tumor initiation and progression. This critical aspect of tumors involves a complex interplay among cancer, stromal, and inflammatory cells, forming an inflammatory TME that promotes tumorigenesis across all stages. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is implicated in modulating various critical processes linked to tumor pathogenesis, including but not limited to the regulation of tumor cell proliferation, invasion, migration, and survival. Furthermore, TRAF6 prominently contributes to various immune and inflammatory pathways. The TRAF6-mediated activation of nuclear factor (NF)-κB in immune cells governs the production of proinflammatory cytokines. These cytokines sustain inflammation and stimulate tumor growth by activating NF-κB in tumor cells. In this review, we discuss various types of tumors, including gastrointestinal cancers, urogenital cancers, breast cancer, lung cancer, head and neck squamous cell carcinoma, uterine fibroids, and glioma. Employing a rigorous and systematic approach, we comprehensively evaluate the functional repertoire and potential roles of TRAF6 in various cancer types, thus highlighting TRAF6 as a compelling and emerging therapeutic target worthy of further investigation and development.

The immune response to arterial damage in a mouse model of intermittent hypoxia: a transcriptomics analysis.

PURPOSE: Mice can develop arterial damage and even atherosclerosis under intermittent hypoxia (IH); however, the specific mechanism of arterial damage induced by IH remains unclear. Hence, this research aimed to illustrate the underlying mechanism linking IH to arterial injury. MATERIALS AND METHODS: The differential gene expression of the thoracic aorta under normoxia or IH mice was analyzed utilizing RNA sequencing. Furthermore, GO, KEGG pathway, and CIBERSORT analyses were carried out. For verification of the expression of candidate genes affected by IH, quantitative RT-qPCR (qRT-PCR) was conducted. Immunohistochemical (IHC) staining revealed immune cell infiltration in the thoracic aorta. RESULTS: The thickness of the intima-media of the mouse aorta was increased, and the fiber structure was disordered under IH. Transcriptomics analysis showed that in the aorta, 1137 upregulated genes and 707 downregulated genes were affected by IH, significantly related to the activation of the immune system and cell adhesion. Furthermore, B cell infiltration around the aorta was observed under IH. CONCLUSIONS: IH might lead to structural changes in the aorta by activating the immune response and enhancing cell adhesion.

FKBP5 genetic variants are associated with respiratory- and sleep-related parameters in Chinese patients with obstructive sleep apnea.

Introduction: Obstructive sleep apnea (OSA) has been associated with psychiatric disorders, especially depression and posttraumatic stress disorder (PTSD). FKBP5 genetic variants have been previously reported to confer the risk of depression and PTSD. This study aimed to investigate the association of single nucleotide polymorphisms (SNPs) in the FKBP5 gene with OSA and OSA-related quantitative traits. Methods: Four SNPs within the FKBP5 gene (rs1360780, rs3800373, rs9296158, rs9470080) were genotyped in 5773 participants with anthropometric and polysomnography data. Linear regression and logistic regression analyses were performed to evaluate the relationship between FKBP5 SNPs and OSA-related traits. Binary logistic regression was used to assess the effect of SNPs on OSA susceptibility. Interacting genes of SNPs were assessed based on the 3DSNP database, and expression quantitative trait loci (eQTL) analysis for SNPs was adopted to examine the correlation of SNPs with gene expression. Gene expression analyses in human brains were performed with the aid of Brain Atlas. Results: In moderate-to-severe OSA patients, all four SNPs were positively associated with AHIREM, and rs9296158 showed the strongest association (ß = 1.724, p = 0.001). Further stratified analyses showed that in men with moderate OSA, rs1360780, rs3800373 and rs9470080 were positively associated with wake time (p = 0.0267, p = 0.0254 and p = 0.0043, respectively). Rs1360780 and rs3800373 were 28 and 29.4%more likely to rate a higher ordered MAI category (OR (95% CI) = 1.280 (1.042 - 1.575), p = 0.019; OR (95% CI) = 1.294 (1.052 - 1.592), p = 0.015, respectively). Rs9296158 and rs9470080 increased the risk of low sleep efficiency by 25.7 and 28.1% (OR (95% CI) = 1.257 (1.003 - 1.575), p = 0.047; OR (95% CI) = 1.281 (1.026-1.6), p = 0.029, respectively). Integrated analysis of eQTL and gene expression patterns revealed that four SNPs may exert their effects by regulating FKBP5, TULP1, and ARMC12. Conclusion: Single nucleotide polymorphisms in the FKBP5 gene were associated with sleep respiratory events in moderate-to-severe OSA patients during REM sleep and associated with sleep architecture variables in men with moderate OSA. FKBP5 variants may be a potential predisposing factor for sleep disorders, especially in REM sleep.

Comprehensive Analysis of N6-Methyladenosine Regulators in the Subcluster Classification and Drug Candidates Prediction of Severe Obstructive Sleep Apnea.

Background: Obstructive sleep apnea (OSA) is the most common type of sleep apnea that impacts the development or progression of many other disorders. Abnormal expression of N6-methyladenosine (m6A) RNA modification regulators have been found relating to a variety of human diseases. However, it is not yet known if m6A regulators are involved in the occurrence and development of OSA. Herein, we aim to explore the impact of m6A modification in severe OSA. Methods: We detected the differentially expressed m6A regulators in severe OSA microarray dataset GSE135917. The least absolute shrinkage and selection operator (LASSO) and support vector machines (SVM) were used to identify the severe OSA-related m6A regulators. Receiver operating characteristic (ROC) curves were performed to screen and verify the diagnostic markers. Consensus clustering algorithm was used to identify m6A patterns. And then, we explored the character of immune microenvironment, molecular functionals, protein-protein interaction networks and miRNA-TF coregulatory networks for each subcluster. Finally, the Connectivity Map (CMap) tools were used to tailor customized treatment strategies for different severe OSA subclusters. An independent dataset GSE38792 was used for validation. Results: We found that HNRNPA2B1, KIAA1429, ALKBH5, YTHDF2, FMR1, IGF2BP1 and IGF2BP3 were dysregulated in severe OSA patients. Among them, IGF2BP3 has a high diagnostic value in both independent datasets. Furthermore, severe OSA patients can be accurately classified into three m6A patterns (subcluster1, subcluster2, subcluster3). The immune response in subcluster3 was more active because it has high M0 Macrophages and M2 Macrophages infiltration and up-regulated human leukocyte antigens (HLAs) expression. Functional analysis showed that representative genes for each subcluster in severe OSA were assigned to histone methyltransferase, ATP synthesis coupled electron transport, virus replication, RNA catabolic, multiple neurodegeneration diseases pathway, et al. Moreover, our finding demonstrated cyclooxygenase inhibitors, several of adrenergic receptor antagonists and histamine receptor antagonists might have a therapeutic effect on severe OSA. Conclusion: Our study presents an overview of the expression pattern and crucial role of m6A regulators in severe OSA, which may provide critical insights for future research and help guide appropriate prevention and treatment options.

Gp130 degradation induced by epirubicin contributes to chemotherapy efficacy.

Two anthracyclines, doxorubicin and epirubicin have been widely used alone or in combination with other antitumor reagents in the chemotherapeutic treatment of various malignancies. Although therapeutic efficacy of anthracyclines has been studied extensively, precise cytotoxic mechanism of these drugs is not been completely elucidated. Here we show that epirubicin-induced degradation of transmembrane protein gp130 contributes to antitumor effect of epirubicin. gp130 is degraded by epirubicin in a proteasome- and autophagy-dependent manner. Epirubicin induces activation of p38-MK2 signaling pathway to phosphorylate gp130 at Ser 782, which results in gp130 internalization and degradation by lysosome. Although mutation of Ser 782 to Ala or Cys in gp130 upregulates global epirubicin-induced autophagy, reduced degradation of gp130 accompanied with enhanced Stat3 phosphorylation at tyrosine 705 is observed. We also show that epirubicin-resistant tumor cells express higher level of gp130. Altogether, our results indicate that degradation of gp130 and subsequent reduction of gp130-Stat3 signaling contributes to epirubicin-induced tumor cell death.

Gene expression profiling provides insights into the immune mechanism of Plutella xylostella midgut to microbial infection.

Insect gut immunity plays a key role in defense against microorganism infection. The knowledge of insect gut immunity has been obtained mostly from Drosophila melanogaster. Little is known about gut immunity in the diamondback moth, Plutella xylostella (L.), a pest destroying cruciferous crops worldwide. In this study, expressions of the immune-related genes in the midgut of P. xylostella orally infected with Staphylococcus aureus, Escherichia coli and Pichia pastoris were profiled by RNA-seq and qRT-PCR approaches. The results revealed that the Toll, IMD, JNK and JAK-STAT pathways and possibly the prophenoloxidase activation system in P. xylostella could be activated by oral infections, and moricins, gloverins and lysozyme2 might act as important effectors against microorganisms. Subsequent knock-down of IMD showed that this gene was involved in regulating the expression of down-stream genes in the IMD pathway. Our work indicates that the Toll, IMD, JNK and JAK-STAT pathways may synergistically modulate immune responses in the P. xylostella midgut, implying a complex and diverse immune system in the midgut of insects.