FOSL1-mediated LINC01566 negatively regulates CD4+ T-cell activation in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. The evidence suggests that the regulation of long noncoding RNAs (lncRNAs) that is mediated by transcription factors (TFs) plays a key role in the pathophysiology of MG. Nevertheless, the detailed molecular mechanisms of lncRNAs in MG remain largely undetermined. METHODS: Using microarray analysis, we analyzed the lncRNA levels in MG. By bioinformatics analysis, LINC01566 was found to potentially play an important role in MG. First, qRT‒PCR was performed to verify the LINC1566 expressions in MG patients. Then, fluorescence in situ hybridization was conducted to determine the localization of LINC01566 in CD4 + T cells. Finally, the impact of LINC01566 knockdown or overexpression on CD4 + T-cell function was also analyzed using flow cytometry and CCK-8 assay. A dual-luciferase reporter assay was used to validate the binding of the TF FOSL1 to the LINC01566 promoter. RESULTS: Based on the lncRNA microarray and differential expression analyses, we identified 563 differentially expressed (DE) lncRNAs, 450 DE mRNAs and 19 DE TFs in MG. We then constructed a lncRNA-TF-mRNA network. Through network analysis, we found that LINC01566 may play a crucial role in MG by regulating T-cell-related pathways. Further experiments indicated that LINC01566 is expressed at low levels in MG patients. Functionally, LINC01566 is primarily distributed in the nucleus and can facilitate CD4 + T-cell apoptosis and inhibit cell proliferation. Mechanistically, we hypothesized that LINC01566 may negatively regulate the expressions of DUSP3, CCR2, FADD, SIRPB1, LGALS3 and SIRPB1, which are involved in the T-cell activation pathway, to further influence the cellular proliferation and apoptosis in MG. Moreover, we found that the effect of LINC01566 on CD4 + T cells in MG was mediated by the TF FOSL1, and in vitro experiments indicated that FOSL1 can bind to the promoter region of LINC01566. CONCLUSIONS: In summary, our research revealed the protective roles of LINC01566 in clinical samples and cellular experiments, illustrating the potential roles and mechanism by which FOSL1/LINC01566 negatively regulates CD4 + T-cell activation in MG.

Artesunate improves learning and memory impairment in rats with vascular cognitive impairment by down-regulating the level of autophagy in cerebral cortex neurons.

Background: Vascular cognitive impairment (VCI) is the second leading cause of dementia. Cognitive impairment is a common consequence of VCI. However, there is no effective treatment for VCI and the underlying mechanism of its pathogenesis remains unclear. This study to investigate whether artesunate (ART) can improve the learning and memory function in rats with VCI by down-regulating he level of autophagy in cerebral cortex neurons. Methods: The models for VCI were the rat bilateral common carotid artery occlusion (BACCO), which were randomized into three groups including the sham operation group (Sham), model + vehicle group (Model) and model + ART group (ART). Then the animal behaviors were recorded, as well as staining the results of cortical neurons. Western blot was performed to determine the protein expressions of LC3BⅡ/Ⅰ, p-AMPK, p-mTOR, and Beclin-1. Results: Behavioral outcomes and the protein expressions in Model group were supposedly affected by the induction of autophagy in cerebral cortex neurons. Compared to the Model group, ART improved memory impairment in VCI rats. And the expression of LC3BⅡ/Ⅰ, p-AMPK/AMPK, Beclin-1 is significant decreased in the ART group, while significant increases of p-mTOR/mTOR were showed. These results suggest that ART improved learning and memory impairment in VCI rats by down-regulating the level of autophagy in cerebral cortex neurons. Conclusion: The results suggest that autophagy occurs in cerebral cortex neurons in rats with VCI. It is speculated that ART can improve learning and memory impairment in VCI rats by down-regulating the level of autophagy in cerebral cortex neurons.

Predicting Secondary Vertebral Compression Fracture After Vertebral Augmentation via CT-Based Machine Learning Radiomics-Clinical Model.

RATIONALE AND OBJECTIVES: Secondary vertebral compression fractures (SVCF) are very common in patients after vertebral augmentation (VA). The aim of this study was to establish a radiomic-based model to predict SVCF and specify appropriate treatment strategies. MATERIALS AND METHODS: Patients diagnosed with osteoporotic vertebral compression fracture (OVCF) and undergoing VA surgery at our center between 2017 and 2021 were subject to a retrospective analysis. Radiological features of the T6-L5 vertebrae were derived from CT images. Clustering analysis, t-test, and LASSO (least absolute shrinkage and selection operator) regression were used to identify the optimization characteristics. A radiological signature model was constructed through the best combination of 13 machine learning algorithms. Radiomics signature was integrated with clinical characteristics into a nomogram for clinical applications. The model reliability was assessed by receiver operating characteristic (ROC) curve, calibration curve, clinical decision analysis (DCA), log-rank test, and confusion matrix. RESULTS: A total of 470 eligible patients (81 with SVCF and 389 without) were identified in the clinical cohort. Eight radiomics features were identified and incorporated into machine learning, and "XGBoost" model showed the best performance. Final logistic nomogram included radiomics signature (P < 0.001), bone cement volume (P = 0.034), and T-scores of L1-L4 (P = 0.001), and showed satisfactory prediction capability in training set (0.986, 95%CI 0.969-1.000) and verification set (0.884, 95%CI 0.823-0.946). CONCLUSION: Our radiomics-clinical model based on machine learning showed potential to prospectively predict SVCF after VA and provide precise treatment strategies.

Administering immunotherapy after anti-vascular targeted therapy improves overall survival of patients with metastatic clear cell renal cell carcinoma.

BACKGROUND: The Food and Drug Administration of the United States has approved several drugs for treating advanced metastatic renal cell carcinoma, including anti-vascular tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Options for first-line therapy include monotherapy or combination therapy. However, selecting a suitable first-line and second-line treatments to improve overall survival remains an unresolved issue. OBJECTIVE: To evaluate the overall survival (OS) and progression-free survival (PFS) of patients with metastatic clear cell renal cell carcinoma (mRCC). Patients were divided into several grouped according to the treatment sequence of TKI and anti PD-1 administration. The overall survival benefit was evaluated based on the order of administration of anti PD-1 and TKI. PATIENTS AND METHODS: In this retrospective propensity-matched cohort study, we identified 135 patients with mRCC treated at the Affiliated Cancer Hospital of Shandong First Medical University from January 1, 2017, to December 31, 2022. These patients had received anti PD-1 treatment as part of their first or second line of therapy. Statistical analysis was performed from June 1, 2023, to August 1, 2023. The primary outcome measure was OS, from the date of diagnosis to death or the last follow-up. PFS was monitored during treatment. Survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. By comparing the complete treatment course of patients, the survival of patients in different groups was compared according to the number of immunotherapy lines. RESULTS: The final cohort comprised 135 patients, of whom 84 received first-line therapy with anti PD-1 (include 6 patients treated with anti PD-1 (tislelizumab, carrelizumab, toripalimab or sintilizumab) alone and 78 patients treated with anti PD-1 combined with anti-vascular TKI (axitinib, sunitinib, solfanitinib or pazopanib)). The remaining 51 patients were treated with anti PD-1 as second-line therapy following an initial regime of TKIs. Patients were initially categorized based on whether anti PD-1 were used in the first-line treatment. It was observed that the OS of patients receiving first-line targeted therapy was higher than those receiving first-line immunotherapy, with a median OS of 33 months versus 15 months. To investigate this outcome further, we refined the patient groups based on the administration sequence of anti PD-1 and TKIs in the treatment regimen. We found that the median PFS of patients with first-line treatments of TKI combined with anti PD-1 was 3.5 months, compared to 14.5 months when TKI combined with anti PD-1 followed first-line TKI (p=0.0092). The median PFS for second-line treatments was 6.5 months versus 15 months (p=0.0014). Similarly, the median OS was 16.66 months and 31.88 months, respectively (p=0.008). CONCLUSIONS: This study indicates that administering immunotherapy following anti-vascular therapy significantly enhances both OS and PFS compared to other sequences of therapies. This finding provides valuable insights and robust data support for clinical decision-making regarding treatment sequencing.

Unearthing New ccr Genes and Staphylococcal Cassette Chromosome Elements in Staphylococci Through Genome Mining.

Staphylococcal cassette chromosome mec (SCCmec) typing is crucial for investigating methicillin-resistant Staphylococcus aureus (MRSA), relying primarily on the combination of ccr and mec gene complexes. To date, 19 ccr genes and 10 ccr gene complexes have been identified, forming 15 SCCmec types. With the vast release of bacterial genome sequences, mining the database for novel ccr gene complexes and SCC/SCCmec elements could enhance MRSA epidemiological studies. In this study, we identified 12 novel ccr genes (6 ccrA, 3 ccrB, and 3 ccrC) through mining of the National Center for Biotechnology Information (NCBI) database, forming 12 novel ccr gene complexes and 10 novel SCC elements. Overexpression of 5 groups of novel Ccr recombinases (CcrA9B3, CcrA10B1, CcrC3, CcrC4, and CcrC5) in a mutant MRSA strain lacking the ccr gene and extrachromosomal circular intermediate (ciSCC) production significantly promoted ciSCC production, demonstrating their biological activity. This discovery provides an opportunity to advance MRSA epidemiological research and develop database-based bacterial typing methods.

A novel PROTAC molecule dBET1 alleviates pathogenesis of experimental autoimmune encephalomyelitis in mice by degrading BRD4.

Neuroinflammation and neurodegeneration are hallmarks of multiple sclerosis (MS). Bromodomain-containing protein 4 (BRD4), a bromodomain and extra-terminal domain (BET) protein family member, is indispensable for the transcription of pro-inflammatory genes. Therefore, inhibiting BRD4 may be a prospective therapeutic approach for modulating the inflammatory response and regulating the course of MS. dBET1, a newly synthesized proteolysis-targeting chimera (PROTAC), exhibits effectively degrades of BRD4. However, the precise effects of dBET1 on MS require further investigation. Therefore, we assessed the effect of dBET1 in experimental autoimmune encephalomyelitis (EAE), a typical MS experimental model. Our findings revealed that BRD4 is mainly expressed in astrocytes and neurons of the spinal cords, and is up-regulated in the spinal cords of EAE mice. The dBET1 attenuated lipopolysaccharide-induced expression of astrocytic pro-inflammatory mediators and inhibited deleterious molecular activity in astrocytes. Correspondingly, dBET1, used in preventive and therapeutic settings, alleviated the behavioral symptoms in EAE mice, as demonstrated by decreased demyelination, alleviated leukocyte infiltration, reduced microglial and astrocyte activation, and diminished inflammatory mediator levels. In addition, dBET1 corrected the imbalance in peripheral T cells and protected blood-brain barrier integrity in EAE mice. The underlying mechanism involved suppressing the phosphoinositide-3-kinase/protein kinase B, mitogen-activated protein kinase /extracellular signal-regulated kinase, and nuclear factor kappa B pathways. In summary, our data strongly suggests that dBET1 is a promising treatment option for MS.

Comparison of Predictive Performance for Pedicle Screw Loosening Between Computed Tomography-Based Hounsfield Units and Magnetic Resonance Imaging-Based Vertebral Bone Quality Score After Lumbar Surgery.

OBJECTIVE: To compare predictive performance for pedicle screw loosening between computed tomography (CT)-based Hounsfield units (HU) and magnetic resonance imaging (MRI)-based vertebral bone quality score (VBQ) after lumbar surgery. METHODS: A retrospective study was conducted on patients who received transforaminal lumbar interbody fusion continuously at our institution from May 2018 to September 2020. On the basis of 12 months' follow-up lumbar radiographs, screw loosening was defined as a clear zone of minimal thickness of ≥1 mm around the pedicle screw on radiography. VBQ score and HU value were measured using preoperative MRI and CT, respectively. Then, we evaluated the predictive performance of these 2 parameters by comparing the receiver operating characteristic curve. RESULTS: In all patients, area under the curve (AUC) of the VBQ score (AUC = 0.752; 95% confidence interval [CI] 0.663-0.841; P < 0.001) was larger than those of the CT HU value (AUC = 0.652; 95% CI 0.558-0.746; P = 0.005), but there was no significant difference between them (PAUC = 0.076). In patients with lumbar spinal stenosis, AUC of VBQ score (AUC = 0.863; 95% CI 0.764-0.961; P < 0.001) was larger than those of the CT HU value (AUC = 0.673; 95% CI 0.513-0.833; P = 0.043), with significant difference (PAUC = 0.003). CONCLUSIONS: MRI-based VBQ score and CT-based HU value have similar performance in predicting pedicle screw loosening after lumbar surgery. Furthermore, in patients with lumbar spinal stenosis, VBQ score demonstrated better predictive ability than HU value.

Bidirectional Association between Sarcopenia and Depressive Symptoms among Chinese Middle- and Older-Aged Adults: Longitudinal Observational Study.

BACKGROUND: The study aimed to examine the bidirectional relationship between sarcopenia and depressive symptoms in a national, community-based cohort study, despite the unclear temporal sequence demonstrated previously. METHODS: Data were derived from four waves (2011 baseline and 2013, 2015, and 2018 follow-ups) of the China Health and Retirement Longitudinal Study (CHARLS). A total of 17,708 participants aged 45 years or older who had baseline data on both sarcopenia status and depressive symptoms in 2011 were included in the study. For the two cohort analyses, a total of 8092 adults without depressive symptoms and 11,292 participants without sarcopenia in 2011 were included. Sarcopenia status was defined according to the Asian Working Group for Sarcopenia 2019 (AWGS 2019) criteria. Depressive symptoms were defined as a score of 20 or higher on the 10-item Center for Epidemiologic Studies Depressive Scale (CES-D-10). Cox proportional hazard regression models were conducted to examine the risk of depressive symptoms and sarcopenia risk, while cross-lagged panel models were used to examine the temporal sequence between depressive symptoms and sarcopenia over time. RESULTS: During a total of 48,305.1 person-years follow-up, 1262 cases of incident depressive symptoms were identified. Sarcopenia exhibited a dose-response relationship with a higher risk of depressive symptoms (HR = 1.7, 95%CI: 1.2-2.3 for sarcopenia, and HR = 1.5, 95%CI: 1.2-1.8 for possible sarcopenia, p trend < 0.001). In the second cohort analysis, 240 incident sarcopenia cases were identified over 39,621.1 person-years. Depressive symptoms (HR = 1.5, 95%CI: 1.2-2.0) are significantly associated with a higher risk of developing sarcopenia after multivariable adjustment (p < 0.001, Cross-lagged panel analyses demonstrated that depressive symptoms were associated with subsequent sarcopenia (ß = 0.003, p < 0.001). Simultaneously, baseline sarcopenia was also associated with subsequent depressive symptoms (ß = 0.428, p < 0.001). CONCLUSION: This study identified a bidirectional relationship between depressive symptoms and sarcopenia. It seems more probable that baseline sarcopenia is associated with subsequent depressive symptoms in a stronger pattern than the reverse pathway. The interlinkage indicated that maintaining normal muscle mass and strength may serve as a crucial intervention strategy for alleviating mood disorders.

The diagnostic potential role of thioredoxin reductase and TXNRD1 in early lung adenocarcinoma: A cohort study.

Background: Lung adenocarcinoma (LUAD) is the primary form of lung cancer, yet the reliable biomarkers for early diagnosis remain insufficient. Thioredoxin reductase (TrxR) is strongly linked to the occurrence, development, and drug resistance of lung cancer, making it a potential biomarker. However, further research is required to assess its diagnostic value in LUAD. Methods: A retrospective analysis was performed on patients who underwent pulmonary nodule resection at our center from 2018 to 2022. Clinical data, including preoperative TrxR levels, imaging, and laboratory characteristics, were identified as study variables. Two prediction models were constructed using multiple logistic regression, and their prediction performance was evaluated comprehensively. Besides, bioinformatics analyses of TrxR coding genes including differential expression, functional enrichment, immune infiltration, drug sensitivity, and single-cell landscape were performed based on TCGA database, which were subsequently validated by Human Protein Atlas. Results: A total of 506 eligible patients (72 benign lesions, 77 AISs, 185 MIAs and 172 IACs) were identified in the clinical cohort. Two TrxR-based models were developed, which were able to distinguish between benign and malignant pulmonary nodules, as well as pathological subtypes of LUAD, respectively. The models exhibited good predictive ability with all AUC values ranging from 0.7 to 0.9. Based on calibration curves and clinical decision analysis, the nomogram models showed high reliability. Functional analysis indicated that TXNRD1 primarily participated in cell cycle and lipid metabolism. Immune infiltration analysis showed that TXNRD1 has a strong association with immune cells and could impact immunotherapy. Then, we identified small molecular compounds that inhibit TXNRD1 and confirmed TXNRD1 expression by single-cell landscape and immunohistochemistry. Conclusion: This study validated the diagnostic value of TrxR and TXNRD1 in clinical cohorts and transcriptional data, respectively. TrxR and TXNRD1 could be used in the risk diagnosis of early LUAD and facilitate personalized treatment strategies.

CD69+ Vδ1γδ T cells are anti-tumor subpopulations in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC), one of the malignancies with a wide expression of stress ligands recognized by Vδ1γδ T cells, has received much attention in adoptive immunotherapy of γδ T cells. In this study, we aimed to identify the potential anti-tumor Vδ1γδ T subpopulations in HCC. METHODS: Healthy donors (HDs) and HCC patients were recruited from the Affiliated Cancer Hospital of Zhengzhou University. Blood and tumor tissue samples were obtained respectively. Bioinformatics methods were used to analyze total γδ T cells and subsets infiltration, overall survival of HCC patients with high and low infiltration level of Vδ1γδ T cells, and IFNG, granzyme A, granzyme B and perforin expression in TRDV1high/lowCD69high/low groups. CD69 expression and Vδ1γδT cells infiltration in HCC were detected by immunofluorescence. Phenotypic analysis of Vδ1γδ T cells in blood and tumor tissue samples were performed by flow cytometry. RESULTS: Vδ1γδ T cells infiltrating in HCC were associated with better clinical outcome. Study in tumor micro-environment (TME) of HCC demonstrated that not total Vδ1γδ T but CD69+ Vδ1γδ subset infiltration was associated with smaller tumor volume. Moreover, HCC patients simultaneously with high TRDV1 and CD69 expression produced more effector molecules and had longer survival time. Since Vδ1γδ T cells in the tumor microenvironment were often difficult to access, we demonstrated that CD69+ Vδ1γδ T cells also existed in peripheral blood mononuclear cells (PBMC) of HCC and displayed enhanced cytotoxic potentials than HDs. Finally, we investigated the functions and found that CD69+ Vδ1γδ T cells exhibited stronger tumor reactivities when challenged by tumor cells. CONCLUSIONS: CD69+ Vδ1γδ T cells are functional Vδ1γδ T cell subsets in patients with HCC. Circulating CD69+ Vδ1γδ T cell is a promising candidate in immunotherapy of HCC.

Application of Short T1 Inversion Recovery Sequence in Increased Signal Intensity Following Cervical Spondylotic Myelopathy.

OBJECTIVES: To compare magnetic resonance (MR) short T1 inversion recovery (STIR) sequence with MR T2-weighted (T2W) sequence for detecting increased signal intensity (ISI) and assessing outcomes of ISI in cervical spondylotic myelopathy (CSM). METHODS: Data of patients with CSM who showed ISI on MR imaging and had undergone cervical spine surgery were retrospectively reviewed. STIR and T2W images were examined to assess signal intensity ratio (SIR), length and grading of the ISI, maximal spinal cord compression, canal narrowing ratio, and ligamentum flavum hypertrophy. The patients were divided into good and poor groups based on their outcomes. χ2 tests and variance analysis were used to assess intergroup differences. Univariate and multivariate logistic regression analyses were performed to identify risk factors for poor outcomes, and receiver operating characteristic curves were plotted to detect prognostic effects. RESULTS: SIR and ISI lengths were significantly different between the STIR and T2 images. In the univariate logistic regression analysis, age, diabetes, SIRT2, SIRSTIR, and ISISTIR grading were significant factors. Accordingly, in the multivariate logistic regression analysis, age, diabetes, SIRT2, and SIRSTIR were included in the model. Among patients with diabetes, we observed a significant difference between SIRT2 and SIRSTIR. CONCLUSIONS: The STIR sequence demonstrated superior capability to the T2W sequence in detecting ISI; however, there was no obvious difference in predicted outcomes. STIR sequence has a better prognostic value than T2W sequence in patients with diabetes who have CSM. ISI grading based on the STIR sequence may be a clinically valuable indicator.

Alterations in the immune landscape characterized by inflammatory activation and immune escape within 12 h after trauma.

BACKGROUND: Trauma is statistically a significant cause of mortality among patients across countries. Nevertheless, the precise correlation between genetic diagnostic markers and the intricate mechanism of trauma remains indistinct. METHODS: Our study exclusively centered on trauma patients and selected three trauma-related datasets from the Gene Expression Omnibus (GEO) database, all of which had blood samples collected within post-traumatic 12 h. Differential gene screening, the WGCNA and Cytoscape software were employed to analyze the two datasets, with a particular emphasis on the top 100 genes selected based on MCC algorithm scores. A logistic diagnostic model was constructed by analyzing the intersection genes in the third dataset, leading to the identification of diagnostic biomarkers with high efficiency. The global immune landscape of these patients was extensively investigated using a multidimensional approach. Meanwhile, the underlying pathological and physiological mechanisms associated with early trauma status are summarized by integrating existing literature. RESULTS: Out of these two GEO datasets, 21 overlapping genes were identified and incorporated into in the logistic diagnostic model constructed in the GSE36809 dataset. A panel of 9 genes was uncovered as a diagnostic biomarker, and their expression and correlation were subsequently verified. Additionally, by virtue of various algorithms, the findings revealed an upregulation of neutrophil expression and a downregulation of CD8+ T cell expression, indicating characteristic early trauma-induced inflammation activation and immune suppression. The correlation observed between the feature genes and immune cells serves to validate the exceptional diagnostic capability of these 9 genes in identifying trauma status and their promising potential for patients who could benefit from targeted immune interventions. Drawing from these findings, the discussion section offers insights into the underlying pathological and physiological mechanisms at play. CONCLUSION: Our research has discovered a novel diagnostic biomarker and unveiled its association with post-traumatic immune alterations. This breakthrough enables accurate and timely diagnosis of early trauma, facilitating the implementation of appropriate healthcare interventions.

Risk factors and mortality of carbapenem-resistant Pseudomonas aeruginosa bloodstream infection in haematology department: A 10-year retrospective study.

OBJECTIVES: This study aims to investigate the risk factors for carbapenem-resistant Pseudomonas aeruginosa bloodstream infection (CRPA-BSI) and identify predictors of outcomes among patients with P. aeruginosa bloodstream infection (PA-BSI). METHODS: A retrospective cohort study was conducted on patients with PA-BSI at Henan Cancer Hospital from 2013 to 2022. RESULTS: Among the 503 incidences analysed, 15.1% of them were CRPA strains. Age, ANC < 100/mmc, receiving antifungal prophylaxis, exposure to carbapenems within the previous 90 days to onset of BSI, and allogeneic HSCT (allo-HSCT) were associated with the development of CRPA-BSI. CRPA-BSI patients experienced significantly higher 28-day mortality rates compared to those with carbapenem-susceptible P. aeruginosa bloodstream infection. Multivariate logistic regression analysis identified age at BSI, active stage of haematological disease, procalcitonin levels, prior corticosteroid treatment, isolation of CRPA, and septic shock as independent predictors of 28-day mortality. CONCLUSIONS: Risk factors for CRPA-BSI include age, ANC < 100/mmc, antifungal prophylaxis, exposure to carbapenems, and allo-HSCT. Additionally, age at BSI, active haematological disease, procalcitonin levels, prior corticosteroid treatment, CRPA isolation, and septic shock contribute to increased mortality rates among patients with PA-BSI.

Microbiome and lung cancer: carcinogenic mechanisms, early cancer diagnosis, and promising microbial therapies.

Microbiomes in the lung, gut, and oral cavity are correlated with lung cancer initiation and progression. While correlations have been preliminarily established in earlier studies, delving into microbe-mediated carcinogenic mechanisms will extend our understanding from correlation to causation. Building upon the causative relationships between microbiome and lung cancer, a novel concept of microbial biomarkers has emerged, mainly encompassing cancer-specific bacteria and circulating microbiome DNA. They might function as noninvasive liquid biopsy techniques for lung cancer early detection. Furthermore, potential microbial therapies have displayed initial efficacy in lung cancer treatment, providing multiple avenues for therapeutic intervention. Herein, we will discuss the molecular mechanisms and signaling pathways through which microbes influence lung cancer initiation and development. Additionally, we will summarize recent findings on microbial biomarkers as a member of tumor liquid biopsy techniques and provide an overview of the latest advances in various microbe-assisted/mediated therapeutic approaches for lung cancer.

Colorimetric and fluorescent independent dual "signal on" biosensor for accurate detection of ochratoxin A based on aptamer-triggered biocatalytic reactions.

Ochratoxin A (OTA) is a hazardous food contaminant with significant health risks. Dual-channel OTA detection is noted for its cross-reference capability and high accuracy. Still, challenges in addressing in-system corrections and "signal off" related false positives and limited signal gains remain. Herein, we developed a dual-channel "signal on" aptasensor with one recognition process and two independent signal outputs for OTA analysis. The OTA aptamer binds to magnetic beads (MBs) and partially hybridizes with a complementary-trigger (cDNA-Trigger) sequence. Adding OTA disrupts the duplex sequence, leading to G-quadruplex (G4) formation and enrichment on the MBs, which then interacts with hemin to catalyze a color signal. Concurrently, the freed cDNA-Trigger catalyzes an enzyme-free DNA circuit, producing a fluorescence signal. The magnetic enrichment and signal amplification strategies make the proposed assay demonstrate excellent sensitivity toward OTA, with limits of detection (LOD) of 0.017 pM in the fluorescence channel and 48.1 pM in the colorimetric channel. Both channels have effectively detected OTA in grape juice and baijiu, demonstrating their applicability and reliability. Moreover, given the widespread use of smartphones globally, a mini-program with a self-correction function was designed to facilitate on-site colorimetric channel monitoring, making OTA detection more accessible and user-friendly.

A disulfidptosis-related lncRNA signature for predicting prognosis and evaluating the tumor immune microenvironment of lung adenocarcinoma.

As a novel form of regulated cell death (RCD), disulfidptosis offering a significant opportunity in better understanding of tumor pathogenesis and therapeutic strategies. Long non-coding RNAs (lncRNAs) regulate the biology functions of tumor cells by engaging with a range of targets. However, the prognostic value of disulfidptosis-related lncRNAs (DRlncRNAs) in lung adenocarcinoma (LUAD) remains unclear. Therefore, our study aimed at establishing a prognostic model for LUAD patients based on DRlncRNAs. RNA-seq data and clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Subsequently, a prognostic model based on DRlncRNAs was constructed using LASSO and COX regression analysis. Patients were stratified into high- and low-risk groups based on their risk scores. Differences between the high-risk and low-risk groups were investigated in terms of overall survival (OS), functional enrichment, tumor immune microenvironment (TIME), somatic mutations, and drug sensitivity. Finally, the role of lncRNA GSEC in LUAD was validated through in vitro experiments. Using the prognostic model consists of 5 DRlncRNAs (AL365181.2, GSEC, AC093673.1, AC012615.1, AL606834.1), the low-risk group exhibited a markedly superior survival in comparison to the high-risk group. The significant differences were observed among patients from different risk groups in OS, immune cell infiltration, immune checkpoint expression, immunotherapy response, and mutation landscape. Experimental results from cellular studies demonstrate the knockdown of lncRNA GSEC leading to a significant reduction in the proliferation and migration abilities of LUAD cells. Our prognostic model, constructed using 5 DRlncRNAs, exhibited the capacity to independently predict the survival of LUAD patients, providing the potentially significant assistance in prognosis prediction, and treatment effects optimization. Moreover, our study established a foundation for further research on disulfidptosis in LUAD and proposed new perspectives for the treatment of LUAD.

Serum Olink Proteomics-Based Identification of Protein Biomarkers Associated with the Immune Response in Ischemic Stroke.

The immune response is considered essential for pathology of ischemic stroke (IS), but it remains unclear which immune response-related proteins exhibit altered expression in IS patients. Here, we used Olink proteomics to examine the expression levels of 92 immune response-related proteins in the sera of IS patients (n = 88) and controls (n = 88), and we found that 59 of these proteins were differentially expressed. Feature variables were screened from the differentially expressed proteins by the least absolute shrinkage and selection operator (LASSO) and the random forest and by determining whether their proteins had an area under the curve (AUC) greater than 0.8. Ultimately, we identified six potential protein biomarkers of IS, namely, MASP1, STC1, HCLS1, CLEC4D, PTH1R, and PIK3AP1, and established a logistic regression model that used these proteins to diagnose IS. The AUCs of the models in the internal validation and the test set were 0.962 (95% confidence interval (CI): 0.895-1.000) and 0.954 (95% CI: 0.884-1.000), respectively, and the same protein detection method was performed in an external independent validation set (AUC: 0.857 (95% CI: 0.801-0.913)). These proteins may play a role in immune regulation via the C-type lectin receptor signaling pathway, the PI3K-AKT signaling pathway, and the B-cell receptor signaling pathway.

Weight change and all-cause and cause-specific mortality: A 25-year follow-up study.

BACKGROUND: Whether the dynamic weight change is an independent risk factor for mortality remains controversial. This study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial (NIT) cohort. METHODS: Body weight of 21,028 healthy residents of Linxian, Henan province, aged 40-69 years was measured two times from 1986 to 1991. Outcome events were prospectively collected up to 2016. Weight maintenance group (weight change <2 kg) or stable normal weight group was treated as the reference. Cox proportional hazard model was performed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the risk of mortality. RESULTS: A total of 21,028 subjects were included in the final analysis. Compared with the weight maintenance group, subjects with weight loss ≥2 kg had an increased risk of death from all-cause (HR All-cause  = 1.14, 95% CI: 1.09-1.19, P  <0.001), cancer (HR Cancer  = 1.12, 95% CI: 1.03-1.21, P  = 0.009), and heart disease (HR Heart diseases  = 1.21, 95% CI: 1.11-1.31, P  <0.001), whereas subjects with weight gain ≥5 kg had 11% (HR Cancer  = 0.89, 95% CI: 0.79-0.99, P  = 0.033) lower risk of cancer mortality and 23% higher risk of stroke mortality (HR Stroke  = 1.23,95% CI: 1.12-1.34, P  <0.001). For the change of weight status, both going from overweight to normal weight and becoming underweight within 5 years could increase the risk of total death (HR Overweight to normal = 1.18, 95% CI: 1.09-1.27; HR Becoming underweight = 1.35, 95% CI: 1.25-1.46) and cancer death (HR Overweight to normal = 1.20, 95% CI: 1.04-1.39; HR Becoming underweight = 1.44, 95% CI: 1.24-1.67), while stable overweight could increase the risk of total death (HR Stable overweight = 1.11, 95% CI: 1.05-1.17) and death from stroke (HR Stable overweight = 1.44, 95% CI: 1.33-1.56). Interaction effects were observed between age and weight change on cancer mortality, as well as between baseline BMI and weight change on all-cause, heart disease, and stroke mortality (all Pinteraction  <0.01). CONCLUSIONS: Weight loss was associated with an increased risk of all-cause, cancer, and heart disease mortality, whereas excessive weight gain and stable overweight were associated with a higher risk of stroke mortality. Efforts of weight management should be taken to improve health status. TRIAL REGISTRATION: https://classic.clinicaltrials.gov/ , NCT00342654.

Upregulation of CENPM promotes breast carcinogenesis by altering immune infiltration.

BACKGROUND: The involvement of centromere protein M (CENPM) in various types of cancer has been established, however, its impact on breast cancer and immune infiltration remains unknown. METHODS: We examined the expression of CENPM in different cancer types by utilizing the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression Pan-Cancer (GEO) databases. Using data from the TCGA, we examined the correlation between the expression of CENPM, the prognosis, and the clinicopathological features of individuals diagnosed with breast cancer. We conducted an enrichment analysis of CENPM using the clusterProfiler R software tool, utilizing data obtained from breast cancer patients and specimens at our institution. In addition to examining the correlation between CENPM expression and genes associated with immune checkpoints, the TIDE algorithm was employed to explore the potential of CENPM as a biomarker for immunotherapy in breast cancer. The impact of CENPM on the growth of breast cancer cells was evaluated through the utilization of the CCK8 test and the colony formation assay. The effect of CENPM on the migration of breast cancer cells was assessed using scratch and transwell assays. RESULTS: Research findings indicate that elevated levels of CENPM are linked to patient outcomes in breast cancer and various clinicopathological features. Furthermore, elevated levels of CENPM expression correlated with decreased levels of CD8 + T cells and mast cells, increased levels of Tregs and Th2, and reduced levels of CD8 + T cells. Additionally, the coexpression of CENPM with the majority of genes related to immune checkpoints indicates its potential to forecast the effectiveness of treatment in breast cancer. Suppression of CENPM hampers the growth and movement of breast tumor cells. CONCLUSIONS: In summary, our study findings indicate that CENPM may serve as a cancer-causing gene in breast cancer and also as a biomarker for predicting the efficacy of immunotherapy. The oncogene CENPM is associated with breast cancer and is involved in cell proliferation and immune infiltration.

MRI-based clinical-radiomics nomogram to predict early neurological deterioration in isolated acute pontine infarction: a two-center study in Northeast China.

OBJECTIVE: To predict the appearance of early neurological deterioration (END) among patients with isolated acute pontine infarction (API) based on magnetic resonance imaging (MRI)-derived radiomics of the infarct site. METHODS: 544 patients with isolated API were recruited from two centers and divided into the training set (n = 344) and the verification set (n = 200). In total, 1702 radiomics characteristics were extracted from each patient. A support vector machine algorithm was used to construct a radiomics signature (rad-score). Subsequently, univariate and multivariate logistic regression (LR) analysis was adopted to filter clinical indicators and establish clinical models. Then, based on the LR algorithm, the rad-score and clinical indicators were integrated to construct the clinical-radiomics model, which was compared with other models. RESULTS: A clinical-radiomics model was established, including the 5 indicators rad-score, age, initial systolic blood pressure, initial National Institute of Health Stroke Scale, and triglyceride. A nomogram was then made based on the model. The nomogram had good predictive accuracy, with an area under the curve (AUC) of 0.966 (95% confidence interval [CI] 0.947-0.985) and 0.920 (95% [CI] 0.873-0.967) in the training and verification sets, respectively. According to the decision curve analysis, the clinical-radiomics model showed better clinical value than the other models. In addition, the calibration curves also showed that the model has excellent consistency. CONCLUSION: The clinical-radiomics model combined MRI-derived radiomics and clinical metrics and may serve as a scoring tool for early prediction of END among patients with isolated API.