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This study aims to explore the link between retinal vein occlusion (RVO), a blinding ocular condition, and alterations in gut microbiota composition, to offer insights into the pathogenesis of RVO. Fecal samples from 25 RVO patients and 11 non-RVO individuals were analyzed using 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC-MS). Significant differences in the abundance of gut microbial species were noted between RVO and non-RVO groups. At the phylum level, the RVO group showed an elevation in the ratio of Firmicutes to Bacteroidetes. At the genus level, the RVO group showed higher abundance in Escherichia_Shigella (P < 0.05) and less abundance in Parabacteroides (P < 0.01) than the non-RVO group. Functional predictions indicated reduced folate synthesis, biotin metabolism, and oxidative phosphorylation, with an increase in butyric acid metabolism in the RVO group. LC-MS analysis showed significant differences in purine metabolism, ABC transporters, and naphthalene degradation pathways, especially purine metabolism. Pearson correlation analysis revealed significant associations between bacterial genera and fecal metabolites. Enrichment analysis highlighted connections between specific metabolites and bacterial genera. The findings showed that the dysregulation of gut microbiota was observed in RVO patients, suggesting the gut microbiota as a potential therapeutic target. Modulating the gut microbiota could be a novel strategy for managing RVO and improving patient outcomes. Furthermore, the study findings suggest the involvement of gut microbial dysbiosis in RVO development, underscoring the significance of understanding its pathogenesis for effective treatment development. IMPORTANCE: Retinal vein occlusion (RVO) is a blinding ocular condition, and understanding its pathogenesis is crucial for developing effective treatments. This study demonstrates significant differences in gut microbiota composition between RVO patients and non-RVO individuals, implicating the involvement of gut microbial dysbiosis in RVO development. Functional predictions and metabolic profiling provide insights into the underlying mechanisms, highlighting potential pathways for therapeutic intervention. These findings suggest that modulating the gut microbiota might be a promising strategy for managing RVO and improving patient outcomes.
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Bactérias , Fezes , Microbioma Gastrointestinal , Metabolômica , RNA Ribossômico 16S , Oclusão da Veia Retiniana , Humanos , Oclusão da Veia Retiniana/metabolismo , Oclusão da Veia Retiniana/microbiologia , Fezes/microbiologia , Masculino , Bactérias/classificação , Bactérias/metabolismo , Bactérias/genética , Bactérias/isolamento & purificação , Pessoa de Meia-Idade , Feminino , RNA Ribossômico 16S/genética , Idoso , Adulto , Cromatografia LíquidaRESUMO
Due to the inherent damage effect, friction heat is commonly undesirable yet inevitable in moving components. Hence, obtaining robust running of mechanical assemblies under high sliding velocity is challenging. Herein, we report an alternative strategy to design robust self-healing lubricity materials by taking advantage of friction heat-driven solid-liquid phase transition employing facile coatings of n-alkanols/epoxy resin. The lubricity performance of composite coatings increased with sliding velocity, leading to a low friction coefficient (0.066) and wear rate (1.968 × 10-7 mm3 N-1 m-1) under 5000 rpm. The low friction was mainly attributed to the controlled phase-transition characteristics of n-alkanols, which absorbed friction heat to release liquid n-alkanols for maintaining intelligent shear interfaces. The low wear was ascribed to the high load-bearing capacity and self-healing property of composite coatings. Our study may guide a common framework to rationally design self-healing lubricant materials via solid-liquid phase transition by utilizing the undesirable (yet inevitable) friction heat. Our approach could achieve the robust, ultralow friction and wear of moving components under harsh working conditions.
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BACKGROUND: Drug resistance poses a significant challenge in cancer treatment, particularly as a leading cause of therapy failure. Cisplatin, the primary drug for lung adenocarcinoma (LUAD) chemotherapy, shows effective treatment outcomes. However, the development of resistance against cisplatin is a major obstacle. Therefore, identifying genes resistant to cisplatin and adopting personalized treatment could significantly improve patient outcomes. METHODS: By examining transcriptome data of cisplatin-resistant LUAD cells from the GEO database, 181 genes associated with cisplatin resistance were identified. Using univariate regression analysis, random forest and multivariate regression analyses, two prognostic genes, E2F7 and FAM83A, were identified. This study developed a prognostic model utilizing E2F7 and FAM83A as key indicators. The Cell Counting Kit 8 assay, Transwell assay, and flow cytometry were used to detect the effects of E2F7 on the proliferation, migration, invasiveness and apoptosis of A549/PC9 cells. Western blotting was used to determine the effect of E2F7 on AKT/mTOR signaling pathway. RESULTS: This study has pinpointed two crucial genes associated with cisplatin resistance, E2F7 and FAM83A, and developed a comprehensive model to assist in the diagnosis, prognosis, and evaluation of relapse risk in LUAD. Analysis revealed that patients at higher risk, according to these genetic markers, had elevated levels of immune checkpoints (PD-L1 and PD-L2). The prognostic and diagnosis values of E2F7 and FAM83A were further confirmed in clinical data. Furthermore, inhibiting E2F7 in lung cancer cells markedly reduced their proliferation, migration, invasion, and increased apoptosis. In vivo experiments corroborated these findings, showing reduced tumor growth and lung metastasis upon E2F7 suppression in lung cancer models. CONCLUSION: Our study affirms the prognostic value of a model based on two DEGs, offering a reliable method for predicting the success of tumor immunotherapy in patients with LUAD. The diagnostic and predictive model based on these genes demonstrates excellent performance. In vitro, reducing E2F7 levels shows antitumor effects by blocking LUAD growth and progression. Further investigation into the molecular mechanisms has highlighted E2F7's effect on the AKT/mTOR signaling pathway, underscoring its therapeutic potential. In the era of personalized medicine, this DEG-based model promises to guide clinical practice.
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BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown. METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts. RESULTS: MICU3 knock out hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, heart with overexpression of MICU3 exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, mice with overexpression of MICU3 exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in hearts with overexpression of MICU3 compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts. CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.
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Proteínas de Ligação ao Cálcio , Cálcio , Camundongos Knockout , Mitocôndrias Cardíacas , Proteínas de Transporte da Membrana Mitocondrial , Miócitos Cardíacos , Animais , Feminino , Humanos , Masculino , Camundongos , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Canais de Cálcio/genética , Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Cardiomegalia/metabolismo , Cardiomegalia/genética , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/genética , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Miócitos Cardíacos/metabolismoRESUMO
Mechanochemical strategies are widely used in various fields, ranging from friction and wear to mechanosynthesis, yet how the mechanical stress activates the chemical reactions at the electronic level is still open. We used first-principles density functional theory to study the rule of the stress-modified electronic states in transmitting mechanical energy to trigger chemical responses for different mechanochemical systems. The electron density redistribution among initial, transition, and final configurations is defined to correlate the energy evolution during reactions. We found that stress-induced changes in electron density redistribution are linearly related to activation energy and reaction energy, indicating the transition from mechanical work to chemical reactivity. The correlation coefficient is defined as the term "interface reactivity coefficient" to evaluate the susceptibility of chemical reactivity to mechanical action for material interfaces. The study may shed light on the electronic mechanism of the mechanochemical reactions behind the fundamental model as well as the mechanochemical phenomena.
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Transjugular intrahepatic portosystemic shunt (TIPS) is a life-saving procedure for patients with severe portal hypertension and persistent variceal bleeding. Stent fracture is a rare and severe complication; however, its cause and mechanisms remain poorly defined. This case helps understand the factors contributing to its occurrence, complications, and subsequent poor outcomes. A 63-year-old male was presented with ruptured bare stent after a TIPS procedure. The upper edge of the bare stent was ruptured, and its fraction subsequently migrated to the entrance of the right atrium. Meanwhile, a mural thrombus was formed in the inferior vena cava. A surgery for the removal of free fracture was planned for preventing the form of pulmonary embolism. Before the surgery, the fracture was shifted to the right inferior pulmonary artery. Therefore, the surgery was canceled for further evaluation. Then, hematemesis suddenly occurred with a high possibility of variceal bleeding and/or gastric ulcer bleeding. Despite comprehensive treatments, the patient symptoms were still worsened with the development of chest tightness, shortness of breath, severe hypoxia, and heart failure. Finally, the patient succumbed to systemic multiorgan failure and death. Taken together, a ruptured unstable stent should be removed as early as the patient is hemodynamically stable, as it is difficult to balance between hemostasis therapy and anticoagulation treatment in patients with liver-cirrhosis-related severe portal hypertension. Physicians should be on high alert of the potential complications of bare stent rapture after TIPS.
Ruptured TIPS stent with a fatal consequence Unstable stent rupture is a life-threatening complication of TIPS and severely complicates the treatment of gastric ulcer bleeding. Early removal of the ruptured stent is necessary to prevent further complications.
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The low wear resistance of macroscale graphene coatings does not match the ultrahigh mechanical strength and chemical inertness of the graphene layer itself; however, the wear mechanism responsible for this issue at low mechanical stress is still unclear. Here, we demonstrate that the susceptibility of the graphene monolayer to wear at its atomic step edges is governed by the mechanochemistry of frictional interfaces. The mechanochemical reactions activated by chemically active SiO2 microspheres result in atomic attrition rather than mechanical damage such as surface fracture and folding by chemically inert diamond tools. Correspondingly, the threshold contact stress for graphene edge wear decreases more than 30 times to the MPa level, and mechanochemical wear can be described well with the mechanically assisted Arrhenius-type kinetic model, i.e., exponential dependence of the removal rate on the contact stress. These findings provide a strategy for improving the antiwear of graphene-based materials by reducing the mechanochemical interactions at tribological interfaces.
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Hyperuricemia is a chronic metabolic disease caused by purine metabolism disorder. And several gene loci and transporter proteins that associated with uric acid transport functions have been identified. Retinol Dehydrogenase 12 (RDH12), recognized for its role in safeguarding photoreceptors, and our study investigated the potential impact of Rdh12 mutations on other organs and diseases, particularly hyperuricemia. We assessed Rdh12 mRNA expression levels in various tissues and conducted serum biochemical analyses in Rdh12-/- mice. Compared with the wild type, significant alterations in serum uric acid levels and kidney-related biochemical indicators have been revealed. Then further analysis, including quantitative RT-PCR of gene expression in the liver and kidney, highlighted variations in the expression levels of specific genes linked to hyperuricemia. And renal histology assessment exposed mild pathological lesions in the kidneys of Rdh12-/- mice. In summary, our study suggests that Rdh12 mutations impact not only retinal function but also contribute to hyperuricemia and renal disease phenotypes in mice. Our finding implies that individuals with Rdh12 mutations may be prone to hyperuricemia and gout, emphasizing the significance of preventive measures and regular examinations in daily life.
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Hiperuricemia , Camundongos , Animais , Hiperuricemia/genética , Ácido Úrico , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , FenótipoRESUMO
BACKGROUND: Famine exposure in childhood is proven to be associated with multiple chornic disease in adult but has not been studied with chronic kidney disease (CKD). AIMS: This study was conducted to identify the relationship between famine exposure during infancy and childhood - specifically, the Chinese famine of 1959-1961 - and the risk of adult-onset chronic kidney disease (CKD) among Chinese individuals. METHODS: This study included 2937 individuals from the Qingdao Diabetes Prevention Program. They were stratified by birth year into infancy-exposed (1956-1958), childhood-exposed (1950-1955) and unexposed (1963-1971) groups. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. CKD was defined as an eGFR of <90 mL/min/1.73 m2. RESULTS: The mean eGFR values for the infancy-exposed and childhood-exposed groups were 107.23 ± 12.53 and 103.23 ± 12.44 mL/min/1.73 m2, respectively, both of which were lower than that of the unexposed group (114.82 ± 13.39 mL/min/1.73 m2; P < 0.05). In the crude model, the odds ratio (OR) for CKD was 2.00 (95% confidence interval (CI): 1.39-2.88) in the infancy-exposed group and 2.92 (95% CI: 2.17-3.93) in the childhood-exposed group. Further adjustments for urban/rural residence, body mass index, age, current smoking, type 2 diabetes, systolic blood pressure, diastolic blood pressure and total cholesterol did not significantly alter the association between famine exposure and CKD. The corresponding ORs were 1.71 (95% CI: 1.17-2.50) and 2.48 (95% CI: 1.81-3.40) for the infancy-exposed and childhood-exposed groups respectively. CONCLUSIONS: Famine exposure during infancy and childhood is associated with a long-term decline in eGFR and an increased adult-onset CKD risk. Early intervention for high-risk individuals may mitigate the risk of adult-onset CKD.
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Fome Epidêmica , Taxa de Filtração Glomerular , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Lactente , Fatores de Risco , Criança , Adulto , China/epidemiologia , Pré-Escolar , IdosoRESUMO
PURPOSE: While the role of drug-eluting beads transarterial chemoembolization (DEB-TACE) for hepatocellular carcinoma (HCC) is established, questions regarding appropriate bead size for use in patients remain. This trial evaluated the effectiveness and safety of DEB-TACE using small-size (≤ 100 µm) microspheres loaded with epirubicin. MATERIALS AND METHODS: This prospective, single-arm, multicenter study enrolled patients diagnosed with HCC who underwent DEB-TACE using 40 (range, 30-50), 75 (range, 60-90), or 100 (range, 75-125) µm epirubicin-loaded microspheres (TANDEM microspheres, Varian Medical). Bead size was at the discretion of treating physicians and based on tumor size and/or vascular structure. The primary outcome measure was 6-month objective response rate (ORR). Secondary outcome measures were 30-day and 3-month ORR, time to tumor progression and extrahepatic spread, proportion of progression-free survival and overall survival (OS) at one year, and incidence of treatment-associated adverse events. RESULTS: Data from 108 patients from ten centers was analyzed. Six-month ORR was 73.3 and 71.3% based on European association for the study of the liver (EASL) and modified response evaluation criteria in solid tumors (mRECIST) criteria, respectively. Thirty-day ORR was 79.6% for both EASL and mRECIST criteria with 3-month ORR being 80.0 and 81.0%, respectively, for each criteria. One-year PPF and OS rate were 60.3 and 94.3%. There was a total of 30 SAEs reported to be likely to definitely associated with microsphere (n = 9), epirubicin (n = 9), or procedure (n = 12) with none resulting in death. CONCLUSION: DEB-TACE using epirubicin-loaded small-sized (≤ 100 µm) microspheres demonstrates promising local tumor control and acceptable safety in patients with HCC. TRIAL REGISTRATION: Clinicaltrials.gov NCT03113955; registered April 14, 2017. Trial Registration Clinicaltrials.gov NCT03113955; registered April 14, 2017. LEVEL OF EVIDENCE: 2, Prospective, Non-randomized, Single-arm, study.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Epirubicina , Neoplasias Hepáticas/patologia , Microesferas , Estudos Prospectivos , Resultado do Tratamento , Quimioembolização Terapêutica/métodos , Doxorrubicina , Estudos RetrospectivosRESUMO
BACKGROUND: The expression of RKIP, TGM2, and CMTM4 in oral squamous cell carcinoma (OSCC) and normal oral tissues was detected and their correlations were analyzed. The relationships between RKIP, TGM2, and CMTM4 and the clinicopathological parameters and prognosis of patients were analyzed. METHODS: Seventy cancerous and adjacent normal tissue samples were selected, recorded in the pathology department, and embedded in paraffin. Protein expression was detected by immunohistochemistry. Statistical software (SPSS 25.0, IBM Corporation) was used for the statistical analysis. The chi-squared (χ2) test was used to analyze the expression of RKIP, TGM2, and CMTM4 proteins and their clinicopathological features. Differences in RKIP, TGM2, and CMTM4 protein levels between OSCC and normal tissues were compared using a χ2 test. Survival analysis was performed using the Kaplan-Meier method, and differences between survival curves were determined using the log-rank test. The effects of RKIP, TGM2, and CMTM4 expression on patient prognosis were analyzed using a multivariate Cox proportional hazards regression model. Pâ <â .05 was considered statistically significant. RESULTS: The expression level of RKIP correlated with age and clinical stage (Pâ <â .05). TGM2 was associated with clinical stage and lymph node metastasis (Pâ <â .05). The expression of CMTM4 increased with a decrease in cancer differentiation. Kaplan-Meier survival analysis suggested that the positive expression of TGM2 and CMTM4 may predict poor prognosis in patients with OSCC. The multivariate Cox proportional hazards regression model suggested that TGM2 could be an independent prognostic factor for patients with OSCC. CONCLUSION: Combined expression of TGM2 and CMTM4 can be used as an indicator to evaluate the risk of metastasis and prognosis of OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas com Domínio MARVEL , Neoplasias Bucais/patologia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Purpose: To assess the impact of transjugular intrahepatic portosystemic shunt (TIPS) on clinical outcomes and liver histology in patients with hepatic sinusoidal obstruction syndrome (HSOS) caused by pyrrolizidine alkaloids (PA), and compare these results with those of patients who received supportive treatment alone. Materials and methods: From June 2015 to August 2022, 164 patients diagnosed with PA-HSOS in six tertiary care centers were retrospectively included in this study and divided into TIPS group (n = 69) and supportive treatment (ST) group (n = 95). The main endpoint was to determine whether TIPS placement could improve survival in PA-HSOS patients. The clinical symptoms associated with portal hypertension were also evaluated in this study. Additionally, a small TIPS-subgroup of 7 patients received liver biopsies before and after TIPS for histological analysis. Results: The incidence of death was markedly lower in the TIPS group than in the ST group (log-rank p = 0.026). Multivariate Cox model revealed that group assignment (hazard ratio (HR) 5.146; 95 % confidence interval (CI) 1.587-16.687; p = 0.006), total bilirubin (HR 1.029; 95 % CI 1.020-1.038; p < 0.001), and INR (HR 13.291; 95 % CI 3.637-48.566; p < 0.001) were independent predictors for mortality. In addition, TIPS placement reduced the risk of complications associated with portal hypertension but did not increase the rate of overt hepatic encephalopathy (log-rank p = 0.731). Furthermore, six of 7 TIPS patients receiving liver biopsies improved after TIPS placement, and one patient developed fibrosis. Conclusions: TIPS placement decreased the mortality and risk of complications associated with portal hypertension. Histological evaluation in a few patients showed a potential improvement by TIPS.
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Carcinoembryonic antigen (CEACAM5), as a broad-spectrum tumor biomarker, plays a crucial role in analyzing the therapeutic efficacy and progression of cancer. Herein, we propose a novel biosensor based on specklegrams of tapered multimode fiber (MMF) and two-dimensional convolutional neural networks (2D-CNNs) for the detection of CEACAM5. The microfiber is modified with CEA antibodies to specifically recognize antigens. The biosensor utilizes the interference effect of tapered MMF to generate highly sensitive specklegrams in response to different CEACAM5 concentrations. A zero mean normalized cross-correlation (ZNCC) function is explored to calculate the image matching degree of the specklegrams. Profiting from the extremely high detection limit of the speckle sensor, variations in the specklegrams of antibody concentrations from 1 to 1000 ng/mL are measured in the experiment. The surface sensitivity of the biosensor is 0.0012 (ng/mL)-1 within a range of 1 to 50 ng/mL. Moreover, a 2D-CNN was introduced to solve the problem of nonlinear detection surface sensitivity variation in a large dynamic range, and in the search for image features to improve evaluation accuracy, achieving more accurate CEACAM5 monitoring, with a maximum detection error of 0.358%. The proposed fiber specklegram biosensing scheme is easy to implement and has great potential in analyzing the postoperative condition of patients.