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PURPOSE: The purpose of this study is to dynamically assess variations in tunnel diameters following anterior cruciate ligament reconstruction (ACLR) and investigate correlations with patient-reported outcomes (PROs) and graft maturity based on signal-to-noise quotient (SNQ). METHODS: Tunnel diameter and tunnel position were measured using three-dimensional models derived from computed tomography (CT) data. Postoperative graft maturity and integration were evaluated using magnetic resonance imaging (MRI). Clinical outcomes were assessed through PROs, which included the International Knee Documentation Committee Subjective Knee Evaluation Form, Knee Injury and Osteoarthritis Outcome Scores and Lysholm scores. The correlation between tunnel enlargement extent, PROs and SNQ values, as well as correlations between confounding factors, tunnel diameter differences and SNQ were analyzed. RESULTS: A total of 73 participants underwent primary ACLR and scheduled follow-ups. At the segment of the articular aperture, the femoral tunnel was enlarged by 32.3% to 10.4 ± 1.6 mm (p < 0.05), and the tibial tunnel was widened by 17.2% to 9.6 ± 1.2 mm (p < 0.05) at the 6-month follow-up. At 1 year postoperatively, diameters at the articular aperture were not further increased on the femoral (n.s.) and tibial (n.s.) sides. In early postoperative follow-up, the femoral tunnel was anteriorly and distally shifted, coupled with posterior and lateral deviation involving the tibial side, exhibiting minimal migration at 1-year follow-up. The degree of tunnel widening was not correlated with PROs and SNQ values. Age, gender, body mass index (BMI), time from surgery to follow-up, concomitant injuries and autograft type were not correlated with tunnel diameter differences and SNQ. CONCLUSIONS: The femoral and tibial bone tunnels exhibited eccentrical widening and gradually stabilized at 1 year following ACLR. Furthermore, the enlarged bone tunnels were not correlated with unsatisfied PROs and inferior graft maturity. LEVEL OF EVIDENCE: Level IV.
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OBJECTIVES: Baker's cyst (BC) is a complex complication of rheumatoid arthritis (RA), with a poor prognosis. This paper aimed to analyze the clinical features and risk factors for BC in patients with RA to assist clinicians in early warning and appropriate action. METHODS: The Clinical features of hospitalized RA patients with knee affected were analyzed retrospectively. The R software was used for the statistical analysis, while logistic regression analyses were used to determine independent risk factors. RESULTS: A total of 367 RA patients with knee affected were studied, and BC was diagnosis in 15.3% of them. The BC group exhibited a higher proportion of knee-only affected than the non-BC group (p < 0.05), while the attributes linked to disease activity exhibited no disparity. Logistic regression analyses selected two independent risk factors for BC: knee-only affected and anemia. 26.8% of patients with BC developed rupture, exhibiting a higher proportion of knee-only affected (p < 0.05), compared to those unruptured. CONCLUSIONS: The occurrence and rupture of BC in RA patients were significantly related to local inflammation, but not to systemic one. Incorporating local treatment may be a more advantageous option compared to solely relying on systemic therapy.
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Epidemiological studies have shown that coke oven emissions (COEs) affect the deterioration of asthma, but has not been proven by experimental results. In this study, we found for the first time that COEs exacerbate allergen house dust mite (HDM)-induced allergic asthma in the mouse model. The findings reveal that airway inflammation, airway remodeling and allergic reaction were aggravated in the COE + HDM combined exposure group compared with the individual exposure group. Mechanism studies indicated higher levels of iron and MDA in the COE + HDM combined exposure group, along with increased expression of Ptgs2 and reduced GPX4 expression. Iron chelator deferoxamine (DFO) effectively inhibited ferroptosis induced by COE synergistically with HDM in vitro. Further studies highlighted the role of ferritinophagy in the COE + HDM-induced ferroptosis. 3-methyladenine (3-MA) could inhibit ferroptosis in the COE + HDM exposure group. Interestingly, we injected DFO intraperitoneally into mice in the combined exposure group and found DFO could significantly inhibit the COE-exacerbated ferroptosis and allergic asthma. Our findings link ferroptosis with COE-exacerbated allergic asthma, implying that ferroptosis may have important therapeutic potential for asthma in patients with occupational exposure of COE.
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A new cocrystalline form of metronidazole (MET) with propyl gallate (PRO), referred to as MET-PRO, has been successfully synthesized and characterized. Structural characterization reveals that MET and PRO are present in a 1:1 ratio within the cocrystal lattice, with one water molecule equivalent incorporated into the structure. This arrangement facilitates the formation of MET-PRO heterodimers and multiple stable units, collectively constructing a three-dimensional supramolecular network. The solubility and permeability of the current cocrystal, along with the parent drug MET, are evaluated under physiological pH conditions. Experimental findings reveal that MET within the cocrystal exhibits a 1.54-2.37 folds increase in solubility and approximately a threefold improvement in permeability compared to its standalone form. Intriguingly, these concurrent enhancements in the physicochemical properties of MET lead to augmented antibacterial activity in vitro, evidenced by a reduction in minimum inhibitory concentration. Even more intriguingly, the enhanced physicochemical properties observed in vitro for the current cocrystal translate into tangible pharmacokinetic benefits in vivo, characterized by prolonged half-life and enhanced bioavailability. Consequently, this research not only introduces a fresh crystal structure for antibacterial medication but also presents approach for optimizing drug properties across in vitro and in vivo settings, while concurrently bolstering the antibacterial effectiveness of MET through pharmaceutical cocrystallization techniques.
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Introduction: Osteoarthritis of the hip or knee has been reported to be linked to an increased risk of frailty. However, a definitive conclusion about whether hip or knee osteoarthritis increases susceptibility to frailty remains elusive. Material and methods: The instrumental variables (IVs) used in this analysis were sourced from publicly available genome-wide association study (GWAS) datasets. We used a two-sample Mendelian randomization analysis to evaluate the plausible causal nexus between hip or knee osteoarthritis and frailty. Results: We included a total of 25 single-nucleotide polymorphisms (SNPs) as instrumental variables through rigorous and comprehensive screening. The results of this analysis suggested that hip or knee osteoarthritis is associated with an elevated risk of frailty. These results remained robust and consistent across multiple calculation methods, including inverse variance weighted (OR = 1.082, 95% CI: 1.0532-1.1125, p = 1.36 × 10-8), MR-Egger regression (OR = 1.175, 95% CI: 1.0162-1.3604, p = 0.040), weighted median estimation (OR = 1.078, 95% CI: 1.0365-1.1219, p = 1.831 × 10-4), weighted mode analysis (OR = 1.089, 95% CI: 1.0078-1.1771, p = 0.041) and simple mode analysis (OR = 1.093, 95% CI: 1.0112-1.1830, p = 0.034). Cochran's Q test showed no evidence of heterogeneity among the IV estimates derived from individual variants, and the MR-Egger regression analysis indicated that the presence of horizontal pleiotropy was unlikely to introduce bias into the results (intercept: -0.0044, p = 0.549). Conclusions: Two-sample Mendelian randomization analysis effectively identified hip or knee osteoarthritis as a contributing risk factor for frailty.
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BACKGROUND: Information about outcomes after revision rotator cuff repair (RCR) is limited. A more thorough investigation of pain, range of motion (ROM), strength, and functional outcomes is needed. Comparing outcomes between primary and revision rotator cuff repair patients can help surgeons guide patient expectations of the revision procedure. The aim of this study was to compare the outcomes of a revision repair group to a control group of primary RCR patients. We expect revision RCR patients to have worse clinical outcomes than primary RCR patients. METHODS: A retrospective review of patients who underwent primary or revision RCR between 2012 to 2020 was performed. The case group included 104 revision patients, and the control group included 414 primary RCR patients. Patient visual analog score (VAS) for pain, ROM, strength, Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES), and Constant-Murley scores were collected at baseline, 12 months, 24 months, and final follow-up. RESULTS: The average final follow-up was 43.9 months for primary patients and 63.8 months for revision patients. 352 primary patients and 55 revision patients had a final follow-up of 2 or more years. By final follow-up, primary patients had less pain than revision patients (Δ of 2.11, P < .0001), but both groups improved overall. Primary patients had significant improvements in forward flexion, external rotation, internal rotation, and abduction at 2 years that were lost by final follow-up, but revision patients did not experience any long-term improvement in ROM. These differences in ROM between groups were not significant. Supraspinatus strength in the revision group did not improve nor decline by final follow-up. By final follow-up, both primary and revision patients had improved SST and ASES scores from baseline. Primary patient ASES scores were 17.9 points higher (P < .0001) than revision patients by final follow-up, and there was no difference between groups in SST scores at this time. CONCLUSION: Revision RCR significantly improves patient pain, SST score, and ASES score at 4 years. Revision patients should not expect to see the improvements in range of motion that may occur after primary repair.
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BACKGROUND: Patients who have been treated with mechanical ventilation for more than 72 hours are susceptible to symptoms such as hypoxia and respiratory muscle fatigue after weaning, which may result in weaning difficulty and delay, as well as an increased incidence of negative emotions such as anxiety and depression. Correct pulmonary rehabilitation exercise technique and timing can improve the weaning success rate, reduce the disability rate, and reduce the incidence of pulmonary infection, as well as reduce medical expenses. OBJECTIVE: This article provides a review of pulmonary rehabilitation interventions for mechanically ventilated patients, searching relevant literature through databases such as CNKI and PubMed, aiming to provide guidance for the successful weaning of mechanically ventilated patients. METHODS: We selected articles related to pulmonary rehabilitation interventions for mechanically ventilated patients from CNKI (China National Knowledge Infrastructure) and PubMed over the years. RESULTS: This article provides a comprehensive review of the research on lung rehabilitation for patients who are mechanically ventilated during the weaning process in an effort to serve as a guide for a successful transition from mechanical ventilation. CONCLUSION: Early pulmonary rehabilitation training can effectively increase the pulmonary function level and ventilation function of patients and reduce the duration of mechanical ventilation and hospitalization, and is an effective, safe, and feasible treatment method.
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Immunotherapy based on immune checkpoint genes (ICGs) has recently made significant progress in the treatment of bladder cancer patients, but many patients still cannot benefit from it. In the present study, we aimed to perform a comprehensive analysis of ICGs in bladder cancer tissues with the aim of evaluating patient responsiveness to immunotherapy and prognosis. We scored ICGs in each BLCA patient from TCGA and GEO databases by using ssGSEA and selected genes that were significantly associated with ICGs scores by using the WCGNA algorithm. NMF clustering analysis was performed to identify different bladder cancer molecular subtypes based on the expression of ICGs-related genes. Based on the immune related genes differentially expressed among subgroups, we further constructed a novel stratified model containing nine genes by uni-COX regression, LASSO regression, SVM algorithm and multi-COX regression. The model and the nomogram constructed based on the model can accurately predict the prognosis of bladder cancer patients. Besides, the patients classified based on this model have large differences in sensitivity to immunotherapy and chemotherapy, which can provide a reference for individualized treatment of bladder cancer.
Subject(s)
Immunotherapy , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/drug therapy , Humans , Immunotherapy/methods , Prognosis , Nomograms , Immune Checkpoint Proteins/genetics , Immune Checkpoint Proteins/metabolism , Gene Expression Regulation, Neoplastic , Biomarkers, Tumor/genetics , Male , Female , Algorithms , Gene Expression ProfilingABSTRACT
Over the past 10 years, hip arthroscopy has been increasingly employed to effectively diagnose and safely treat a range of hip pathologies. With research related to hip arthroscopy continually expanding, the number of articles connected with hip arthroscopy has also consistently grown. We aimed to investigate trends and hotspots in hip arthroscopy-related research, and analyze the top 100 most-cited articles on hip arthroscopy. We searched for ("hip arthroscopy") AND ("article" OR "review") AND "English" in the Web of Science database from 1900 to 2022, which was used to obtain all publications relating to hip arthroscopy. Distribution of country, affiliated institution, journal, authors, citation frequency and keywords were analyzed using VOSviewer. A total of 1094 articles were selected from the Web of Science Core Collection (WoSCC) from 1900 to 2022. The number of publications concerning hip arthroscopy displayed an ascending trend over time. Among the countries, the United States emerged as the largest contributor to the number of articles. The highest prolific institution was American Hip Institute. Among the journals, the highest-ranking journal was "Arthroscopy-the Journal of Arthroscopic and Related Surgery," with 8316 citation counts and 262 articles. The area of greatest research interest was diagnosis and therapy in the field. The scientific articles on the subject of hip arthroscopy have risen continuously in recent years. The United States was the most influential country and made the most significant contributions to this field globally. We identified the research direction and trend for the first time and provided the most recent bibliometric analysis on hip arthroscopy, which may assist researchers in conducting studies on hip arthroscopy.
Subject(s)
Arthroscopy , Bibliometrics , Biomedical Research , Arthroscopy/trends , Arthroscopy/statistics & numerical data , Arthroscopy/methods , Humans , Biomedical Research/trends , Biomedical Research/statistics & numerical data , Hip Joint/surgery , Periodicals as Topic/statistics & numerical data , Periodicals as Topic/trendsABSTRACT
Background: Tiered trauma team activation (TTA) allows systems to optimally allocate resources to an injured patient. Target undertriage and overtriage rates of <5% and <35% are difficult for centers to achieve, and performance variability exists. The objective of this study was to optimize and externally validate a previously developed hospital trauma triage prediction model to predict the need for emergent intervention in 6 hours (NEI-6), an indicator of need for a full TTA. Methods: The model was previously developed and internally validated using data from 31 US trauma centers. Data were collected prospectively at five sites using a mobile application which hosted the NEI-6 model. A weighted multiple logistic regression model was used to retrain and optimize the model using the original data set and a portion of data from one of the prospective sites. The remaining data from the five sites were designated for external validation. The area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC) were used to assess the validation cohort. Subanalyses were performed for age, race, and mechanism of injury. Results: 14 421 patients were included in the training data set and 2476 patients in the external validation data set across five sites. On validation, the model had an overall undertriage rate of 9.1% and overtriage rate of 53.7%, with an AUROC of 0.80 and an AUPRC of 0.63. Blunt injury had an undertriage rate of 8.8%, whereas penetrating injury had 31.2%. For those aged ≥65, the undertriage rate was 8.4%, and for Black or African American patients the undertriage rate was 7.7%. Conclusion: The optimized and externally validated NEI-6 model approaches the recommended undertriage and overtriage rates while significantly reducing variability of TTA across centers for blunt trauma patients. The model performs well for populations that traditionally have high rates of undertriage. Level of evidence: 2.
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BACKGROUND: In many different plants, including Dorstenia and Psoralea corylifolia L., Isobavachalcone (IBC) is a naturally occurring flavonoid chemical having a range of biological actions, including anti-inflammatory, immunomodulatory, and anti-bacterial. The "Theory of Medicinal Properties" of the Tang Dynasty states that Psoralea corylifolia L. has the ability to alleviate discomfort in the knees and waist. One of the most widespread chronic illnesses, osteoarthritis (OA), is characterized by stiffness and discomfort in the joints. However, there hasn't been much research done on the effectiveness and underlying processes of IBC in the treatment of osteoarthritis. AIM OF THE STUDY: To investigate the potential efficacy and mechanism of IBC in treating osteoarthritis, we adopted an integrated strategy of network pharmacology, molecular docking and experiment assessment. MATERIALS AND METHODS: The purpose of this research was to determine the impact of IBC on OA and the underlying mechanisms. IBC and OA possible targets and processes were predicted using network pharmacology, including the relationship between IBC and OA intersection targets, Cytoscape protein-protein interaction (PPI) to obtain key potential targets, and GO and KEGG pathway enrichment analysis to reveal the probable mechanism of IBC on OA. Following that, in vitro tests were carried out to confirm the expected underlying processes. Finally, in vivo tests clarified IBC's therapeutic efficacy on OA. RESULTS: We anticipated and validated that the impact of IBC on osteoarthritis is mostly controlled by the PI3K-AKT-NF-κB signaling pathway by combining the findings of network pharmacology analysis, molecular docking and Experiment Validation. CONCLUSIONS: This study reveals the IBC has potential to delay OA development.
Subject(s)
Chalcones , Drugs, Chinese Herbal , Fabaceae , Osteoarthritis , Molecular Docking Simulation , Network Pharmacology , Phosphatidylinositol 3-Kinases , Osteoarthritis/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic useABSTRACT
ABSTRACT: Fibrosis, which is a manifestation of the physiological response to injury characterized by excessive accumulation of extracellular matrix components, is a ubiquitous outcome of the repair process. However, in cases of repetitive or severe injury, fibrosis may become dysregulated, leading to a pathological state and organ failure. In recent years, a novel form of regulated cell death, referred to as ferroptosis, has been identified as a possible contributor to fibrosis; it is characterized by iron-mediated lipid peroxidation. It has garnered attention due to the growing body of evidence linking ferroptosis and fibrogenesis, which is believed to be driven by underlying inflammation and immune responses. Despite the increasing interest in the relationship between ferroptosis and fibrosis, a comprehensive understanding of the precise role that ferroptosis plays in the formation of fibrotic tissue remains limited. This review seeks to synthesize previous research related to the topic. We categorized the different direct and indirect mechanisms by which ferroptosis may contribute to fibrosis into three categories: (1) iron overload toxicity; (2) ferroptosis-evoked necroinflammation, with a focus on ferroptosis and macrophage interplay; and (3) ferroptosis-associated pro-fibrotic factors and pathways. Furthermore, the review considers the potential implications of these findings and highlights the utilization of ferroptosis-targeted therapies as a promising strategy for mitigating the progression of fibrosis. In conclusion, novel anti-fibrotic treatments targeting ferroptosis could be an effective treatment for fibrosis.
Subject(s)
Ferroptosis , Humans , Inflammation , Lipid Peroxidation , Macrophages , FibrosisABSTRACT
Osteoarthritis (OA) is one of the most common joint diseases, there are no effective disease-modifying drugs, and the pathological mechanisms of OA need further investigation. Here, we show that H3K36 methylations were decreased in senescent chondrocytes and age-related osteoarthritic cartilage. Prrx1-Cre inducible H3.3K36M transgenic mice showed articular cartilage destruction and osteophyte formation. Conditional knockout Nsd1Prrx1-Cre mice, but not Nsd2Prrx1-Cre or Setd2Prrx1-Cre mice, replicated the phenotype of K36M/+; Prrx1-Cre mice. Immunostaining results showed decreased anabolic and increased catabolic activities in Nsd1Prrx1-Cre mice, along with decreased chondrogenic differentiation. Transcriptome and ChIP-seq data revealed that Osr2 was a key factor affected by Nsd1. Intra-articular delivery of Osr2 adenovirus effectively improved the homeostasis of articular cartilage in Nsd1Prrx1-Cre mice. In human osteoarthritic cartilages, both mRNA and protein levels of NSD1 and OSR2 were decreased. Our results indicate that NSD1-induced H3K36 methylations and OSR2 expression play important roles in articular cartilage homeostasis and OA. Targeting H3K36 methylation and OSR2 would be a novel strategy for OA treatment.
Subject(s)
Cartilage, Articular , Osteoarthritis , Mice , Humans , Animals , Chondrocytes/metabolism , Methyltransferases/metabolism , Osteoarthritis/pathology , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Mice, Transgenic , Homeostasis , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolismABSTRACT
Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.
Subject(s)
Autism Spectrum Disorder , Gene Editing , Animals , Mice , Male , Autism Spectrum Disorder/genetics , Brain , Mutation/genetics , MEF2 Transcription Factors/geneticsABSTRACT
Osteoarthritis (OA), a prevalent degenerative condition, occurs due to the deterioration of joint tissues and cells. Consequently, safeguarding chondrocytes against damage caused by inflammation is an area of future research emphasis. There is growing evidence that Ergolide (ERG) has multiple biological functions. Nevertheless, it is still uncertain whether it can hinder the advancement of OA. In this study, we investigate the ERG's potential to reduce inflammation and protect cartilage. ERG treatment in vitro effectively inhibited the excessive production of pro-inflammatory substances, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and tumor necrosis factor-α (TNF-α), leading to their complete suppression. Furthermore, ERG suppressed the production of matrix-degrading enzymes (ADAMTS-5) and matrix metalloproteinase 13 (MMP13), consequently impeding the breakdown of extracellular matrix (ECM) and restraining the synthesis of collagenase II and Aggrecan. Through the P38/MAPK pathway, we discovered that ERG hinders the activation of NF-κB in chondrocytes induced by IL-1ß. The protective effect of ERG was enhanced by the p38 MAPK inhibitor SB203580. In vivo, ERG further demonstrated protective effects on cartilage in animal models of DMM. In conclusion, the study has discovered that ERG exhibits innovative therapeutic potential in the context of OA.
Subject(s)
Anti-Inflammatory Agents , Lactones , Osteoarthritis , Sesquiterpenes , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/metabolism , Osteoarthritis/metabolism , Inflammation/drug therapy , NF-kappa B/metabolism , Chondrocytes , p38 Mitogen-Activated Protein Kinases/metabolism , Interleukin-1beta/metabolism , Cyclooxygenase 2/metabolism , Cells, CulturedABSTRACT
Selenium plays a crucial role as a micronutrient, primarily exerting its biological functions through selenoproteins. It has been established that selenium deficiency adversely impacts cartilage development, leading to alterations in chondrocyte function. In regions with low selenium intake, endemic osteochondrosis has been documented, characterized by compromised growth plate and articular cartilage formation. Vascular endothelial growth factor (VEGF) stands out as a pivotal angiogenic factor, with elevated levels contributing significantly to vascular invasion into chondrocytes. This VEGF-mediated invasion serves as a key signal, prompting morphological changes in the growth plate and initiating cartilage remodeling. In animal models, the selenium deficiency group exhibited heightened levels of the cartilage damage marker matrix metalloproteinases 13 (MMP13). This resulted in articular cartilage degeneration, accompanied by a substantial increase in VEGF expression within the growth plate and articular cartilage, as compared to the normal group. In a chondrogenic progenitor cell (CPC) differentiation model, insufficient selenium induced chondrocyte damage and upregulated inflammatory factors such as inducible NO synthase (iNOS) and cyclooxygenase-2 (COX2). The selenium-deficient groups showed elevated expressions of VEGF, VEGFR2, MMP13, Collagen X, and Angiopoietin 1, accelerating the degradation of the extracellular matrix (ECM), which further promoted the development of cartilage-related diseases. Taken together, these findings provide novel insights for a better understanding of the role of low selenium in cartilage degeneration and angiogenesis. They shed light on the intricate influence of low selenium levels on the development of articular cartilage, emphasizing the interconnected pathways and processes involved.
Subject(s)
Cartilage, Articular , Cell Differentiation , Chondrocytes , Selenium , Vascular Endothelial Growth Factor A , Selenium/deficiency , Selenium/metabolism , Animals , Vascular Endothelial Growth Factor A/metabolism , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Chondrocytes/metabolism , Chondrocytes/pathology , Matrix Metalloproteinase 13/metabolism , Mice , Cyclooxygenase 2/metabolism , Male , Cells, Cultured , ChondrogenesisABSTRACT
An unconventional P/N/Si-free fire safety of epoxy at an ultralow loading with a significantly improved mechanical robustness and toughness via a mere nanocomposite technique is a great challenge. To achieve the goal, a proof of concept is proposed associated with a hierarchical manipulation of catalysis-tailored FexSy ultrathin nanosheets on organic-layered double hydroxide (LDH-DBS@FexSy) toward the formation of porous piling structure via a self-sacrificing conversion of metal-organic framework. A sufficient characterization certified the targeted architecture and composition. A P/N/Si-free ultralow loading of 2 wt % LDH-DBS@FexSy (i.e., 0.6 wt % FexSy) imparted epoxy with UL-94 V-0 rating, a 36.1% reduction of peak heat release rate, as well as a pronounced fire-protection feature. A systematic contrastive investigation evidenced a time-dependent fire-shielding effect induced by a featured catalysis-tailored ultrafast charring behavior at the interface of epoxy and LDH nanosheets. Intriguingly, the tensile strength, impact strength, and flexural strength were simultaneously enhanced by 62.2, 185.4, and 62.9%, respectively, with a 0.6 wt % incorporation of FexSy hierarchy on the basis of a "root-soil"-inspired interfacial "interlocking" structure. In perspective, an integrated manipulation of an interface catalysis-tailored ultrafast charring and hierarchical "interlocking" construction offer an effective balance of the fire safety, mechanical robustness, and toughness of polymers.
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Oxidative stress is closely linked to tumor initiation and development, conferring a survival advantage to cancer cells. Therefore, understanding cancer cells' antioxidant molecular mechanisms is crucial to cancer therapy. In this study, we discovered that H2O2-induced oxidative stress increased Nrf3 expression in colon cancer cells. Overexpression of Nrf3 decreased H2O2-mediated cytotoxicity and apoptosis. Furthermore, Nrf3 reduced reactive oxygen species levels and malondialdehyde concentrations after H2O2 treatment. Mechanistically, H2O2-mediated cell apoptosis involves multiple signaling proteins, including Akt, bcl-2, JNK, and p38. An increase in Nrf3 expression in colon cancer cells treated with H2O2 partly reversed Akt/Bcl-2 inhibition, whereas it decreased activation of p38 and JNK. In addition, we found that increasing Nrf3 decreased stress-associated chemical-induced cell death, resulting in drug resistance. According to these results, Nrf3 is critical for drug resistance and oxidant adaptation.
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This study aimed at establishing more accurate predictive models based on novel machine learning algorithms, with the overarching goal of providing clinicians with effective decision-making assistance. We retrospectively analyzed the breast cancer patients recorded in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2016. Multivariable logistic regression analyses were used to identify risk factors for bone metastases in breast cancer, whereas Cox proportional hazards regression analyses were used to identify prognostic factors for breast cancer with bone metastasis (BCBM). Based on the identified risk and prognostic factors, we developed diagnostic and prognostic models that incorporate six machine learning classifiers. We then used the area under the receiver operating characteristic (ROC) curve (AUC), learning curve, precision curve, calibration plot, and decision curve analysis to evaluate performance of the machine learning models. Univariable and multivariable logistic regression analyses showed that bone metastases were significantly associated with age, race, sex, grade, T stage, N stage, surgery, radiotherapy, chemotherapy, tumor size, brain metastasis, liver metastasis, lung metastasis, breast subtype, and PR. Univariate and multivariate Cox regression analyses revealed that age, race, marital status, grade, surgery, radiotherapy, chemotherapy, brain metastasis, liver metastasis, lung metastasis, breast subtype, ER, and PR were closely associated with the prognosis of BCBM. Among the six machine learning models, the XGBoost algorithm predicted the most accurate results (Diagnostic model AUC = 0.98; Prognostic model AUC = 0.88). According to the Shapley additive explanations (SHAP), the most critical feature of the diagnostic model was surgery, followed by N stage. Interestingly, surgery was also the most critical feature of prognostic model, followed by liver metastasis. Based on the XGBoost algorithm, we could effectively predict the diagnosis and survival of bone metastasis in breast cancer and provide targeted references for the treatment of BCBM patients.
Subject(s)
Bone Neoplasms , Brain Neoplasms , Breast Neoplasms , Liver Neoplasms , Lung Neoplasms , Humans , Female , Breast Neoplasms/diagnosis , Retrospective Studies , Bone Neoplasms/diagnosis , Liver Neoplasms/diagnosis , Machine LearningABSTRACT
BACKGROUND: As a member of the mitochondrial ribosomal protein family, mitochondrial ribosomal protein L13 (MRPL13) is responsible for synthesizing mitochondrial proteins in cells. Several studies have indicated that MRPL13 is associated with the proliferation cycle, migration ability, apoptosis and autophagy of cancer cells. However, a thorough examination of MRPL13 across cancers remains uncertain. Therefore, we tried to clarify the relationship between MRPL13 and pan-cancer, and verified it in lung adenocarcinoma by various methods. Finally, our research is expected to reveal new targets for pan-cancer treatment and improve the prognosis of cancer patients. METHODS: Using bioinformatics tools, we quantified the differential expression of MRPL13 between cancer tissues and corresponding or noncorresponding normal tissues across cancers. We also analyzed the relationships between MRPL13 expression levels and several factors, including diagnosis, prognosis, mutation, functional signaling pathways, immune infiltration, RNA modification, and the relationship with cuproptosis-related genes. Furthermore, we studied the relationship between the expression level of MRPL13 across cancers and the change in cancer functional status through single-cell data. In addition, quantitative experiments (PCR and Western blot) proved that the expression of MRPL13 was significantly different between LUAD and control samples. Finally, the effect of knocking out MRPL13 on cancer cells was compared by gene silencing experiments. In summary, we used a combination of bioinformatics and experimental applications to study the potential roles of MRPL13 in cancer. RESULTS: After conducting a multidimensional analysis, we found that the application of MRPL13 multigroup analysis can effectively improve the diagnostic efficiency of various cancers and predict the prognosis of cancer. Moreover, MRPL13 in pan-cancer is related to the cancer immune infiltration pattern, methylation level and cuproptosis-related genes. Furthermore, single-cell data analysis showed that the modules of metastasis, EMT, cell cycle, DNA repair, invasion, DNA damage and proliferation were positively correlated with the expression of MRPL13 in LUAD (Lung adenocarcinoma), while the modules of hypoxia and inflammation were negatively correlated. Moreover, through quantitative experiments, we observed higher expression of MRPL13 in cancer tissues at the RNA or protein level. Knockdown of MRPL13 in LUAD led to decreased cancer cell survival, delayed tumor division and migration, reduced invasion, and increased cancer cell apoptosis. CONCLUSIONS: Our study demonstrates the potential of using MRPL13 as a molecular biomarker for diagnosing and suggesting the prognosis of certain malignant tumors. Furthermore, our research shows that MRPL13 may be an effective therapeutic target for lung adenocarcinoma.