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Molecular-based multiferroic materials that possess ferroelectric and ferroelastic orders simultaneously have attracted tremendous attention for their potential applications in multiple-state memory devices, molecular switches, and information storage systems. However, it is still a great challenge to effectively construct novel molecular-based multiferroic materials with multifunctionalities. Generally, the structure of these materials possess high symmetry at high temperatures, while processing an obvious order-disorder or displacement-type ferroelastic or ferroelectric phase transition triggered by symmetry breaking during the cooling processes. Therefore, these materials can only function below the Curie temperature (Tc), the low of which is a severe impediment to their practical application. Despite great efforts to elevate Tc, designing single-phase crystalline materials that exhibit multiferroic orders above room temperature remains a challenge. Here, an inverse temperature symmetry-breaking phenomenon was achieved in [FPM][Fe3(µ3-O)(µ-O2CH)8] (FPM stands for 3-(3-formylamino-propyl)-3,4,5,6-tetrahydropyrimidin-1-ium, which acts as the counterions and the rotor component in the network), enabling a ferroelastoelectric phase at a temperature higher than Tc (365 K). Upon heating from room temperature, two-step distinct symmetry breaking with the mm2Fm species leads to the coexistence of ferroelasticity and ferroelectricity in the temperature interval of 365-426 K. In the first step, the FPM cations undergo a conformational flip-induced inverse temperature symmetry breaking; in the second step, a typical ordered-disordered motion-induced symmetry breaking phase transition can be observed, and the abnormal inverse temperature symmetry breaking is unprecedented. Except for the multistep ferroelectric and ferroelastic switching, this complex also exhibits fascinating nonlinear optical switching properties. These discoveries not only signify an important step in designing novel molecular-based multiferroic materials with high working temperatures, but also inspire their multifunctional applications such as multistep switches.
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BACKGROUND: Fatigue is one of the most common neurological symptoms reported post coronavirus disease 2019 (COVID-19) infection. In order to establish effective early intervention strategies, more emphasis should be placed on the correlation between fatigue and cortical neurophysiological changes, especially in healthcare workers, who are at a heightened risk of COVID-19 infection. METHODS: A prospective cohort study was conducted involving 29 COVID-19 medical workers and 24 healthy controls. The assessment included fatigue, sleep and health quality, psychological status, and physical capacity. Functional near-infrared spectroscopy (fNIRS) was employed to detect activation of brain regions. Bilateral primary motor cortex (M1) excitabilities were measured using single- and paired-pulse transcranial magnetic stimulation. Outcomes were assessed at 1, 3, and 6 months into the disease course. RESULTS: At 1-month post-COVID-19 infection, 37.9% of patients experienced severe fatigue symptoms, dropping to 10.3% at 3 months. Interestingly, the remarkable decreased activation/excitability of bilateral prefrontal lobe (PFC) and M1 were closely linked to fatigue symptoms after COVID-19. Notably, greater increase in M1 region excitability correlated with more significant fatigue improvement. Re-infected patients exhibited lower levels of brain activation and excitability compared to single-infection patients. CONCLUSIONS: Both single infection and reinfection of COVID-19 lead to decreased activation and excitability of the PFC and M1. The degree of excitability improvement in the M1 region correlates with a greater recovery in fatigue. Based on these findings, targeted interventions to enhance and regulate the excitability of M1 may represent a novel strategy for COVID-19 early rehabilitation. TRIAL REGISTRATION: The Ethics Review Committee of Xijing Hospital, No. KY20232051-F-1; www.chictr.org.cn , ChiCTR2300068444.
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COVID-19 , Fatiga , Personal de Salud , Corteza Motora , Corteza Prefrontal , Estimulación Magnética Transcraneal , Humanos , COVID-19/fisiopatología , Fatiga/fisiopatología , Masculino , Femenino , Estudios Longitudinales , Adulto , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Motora/fisiopatología , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , Estudios Prospectivos , Espectroscopía Infrarroja Corta , Estudios de CohortesRESUMEN
BACKGROUND: Despite improved treatments for acute myocardial infarction (AMI), myocardial fibrosis remains a key driver of adverse left ventricular (LV) remodeling and increased mortality. Fibroblast activation and proliferation significantly contribute to this process by enhancing cardiac fibrosis, which can lead to detrimental changes in LV structure. This study evaluates the effectiveness of 99mTc-labeled fibroblast activation protein inhibitor (99mTc-HFAPi) SPECT imaging in predicting LV remodeling over 12 months in post-AMI patients. METHODS: A cohort of 58 AMI patients (46 males, median age 61 [53, 67] years) underwent baseline 99mTc-HFAPi imaging (5 ± 2 days post-MI), perfusion imaging (6 ± 2 days post-MI), and echocardiography (2 ± 2 days post-MI). Additionally, 15 patients had follow-up 99mTc-HFAPi and perfusion imaging, while 30 patients had follow-up echocardiography. Myocardial 99mTc-HFAPi activity was assessed at the patient level. LV remodeling was defined as a ≥10% increase in LV end-diastolic diameter (LVEDD) or LV end-systolic diameter (LVESD) from baseline to follow-up echocardiography. RESULTS: AMI patients displayed localized but non-uniform 99mTc-HFAPi uptake, exceeding perfusion defects. Baseline 99mTc-HFAPi activity exhibited significant correlations with BNPmax, LDHmax, cTNImax, and WBCmax, inversely correlating with LVEF. After 12 months, 11 patients (36.66%) experienced LV remodeling. Univariate regression analysis demonstrated an association between baseline 99mTc-HFAPi uptake extent and LV remodeling (OR = 2.14, 95%CI, 1.04, 4.39, P = 0.038). CONCLUSIONS: 99mTc-HFAPi SPECT imaging holds promise in predicting LV remodeling post-MI, providing valuable insights for patient management and prognosis.
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Most of the porous materials used for acetylene/carbon dioxide separation have the problems of poor stability and high energy requirements for regeneration, which significantly hinder their practical application in industries. Here, we report a novel calcium-based metal-organic framework (NKM-123) with excellent chemical stability against water, acids, and bases. Additionally, it has exceptional thermal stability, retaining its structural integrity at temperatures up to 300 °C. This material exhibits promising potential for separating C2H2 and CO2 gases. Furthermore, it demonstrates an adsorption heat of 29.3 kJ mol-1 for C2H2, which is lower than that observed in the majority of MOFs used for C2H2/CO2 separations. The preferential adsorption of C2H2 over that of CO2 is confirmed by dispersion-corrected density functional theory (DFT-D) calculations. In addition, the potential of industrial feasibility of NKM-123 for C2H2/CO2 separation is confirmed by transient breakthrough tests. The robust cycle performance and structural stability of NKM-123 during multiple breakthrough tests show great potential in the industrial separation of light hydrocarbons.
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BACKGROUND: After spinal cord injury (SCI), a large number of survivors suffer from severe motor dysfunction (MD). Although the injury site is in the spinal cord, excitability significantly decreases in the primary motor cortex (M1), especially in the lower extremity (LE) area. Unfortunately, M1 LE area-targeted repetitive transcranial magnetic stimulation (rTMS) has not achieved significant motor improvement in individuals with SCI. A recent study reported that the M1 hand area in individuals with SCl contains a compositional code (the movement-coding component of neural activity) that links matching movements from the upper extremities (UE) and the LE. However, the correlation between bilateral M1 hand area excitability and overall functional recovery is unknown. OBJECTIVE: To clarify the changes in the excitability of the bilateral M1 hand area after SCI and its correlation with motor recovery, we aim to specify the therapeutic parameters of rTMS for SCI motor rehabilitation. METHODS: This study is a 12-month prospective cohort study. The neurophysiological and overall functional status of the participants will be assessed. The primary outcomes included single-pulse and paired-pulse TMS. The second outcome included functional near-infrared spectroscopy (fNIRS) measurements. Overall functional status included total motor score, modified Ashworth scale score, ASIA Impairment Scale grade, spinal cord independence measure and modified Barthel index. The data will be recorded for individuals with SCI at disease durations of 1 month, 2 months, 4 months, 6 months and 12 months. The matched healthy controls will be measured during the same period of time after recruitment. DISCUSSION: The present study is the first to analyze the role of bilateral M1 hand area excitability changes in the evaluation and prediction of overall functional recovery (including motor function and activities of daily living) after SCI, which will further expand the traditional theory of the predominant role of M1, optimize the current rTMS treatment, and explore the brain-computer interface design for individuals with SCI. TRIAL REGISTRATION NUMBER: ChiCTR2300068831.
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Mano , Corteza Motora , Recuperación de la Función , Traumatismos de la Médula Espinal , Estimulación Magnética Transcraneal , Humanos , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Recuperación de la Función/fisiología , Mano/fisiopatología , Estimulación Magnética Transcraneal/métodos , Corteza Motora/fisiopatología , Estudios Prospectivos , Potenciales Evocados Motores/fisiología , Masculino , Adulto , Femenino , Estudios de Cohortes , Persona de Mediana Edad , Espectroscopía Infrarroja Corta/métodosRESUMEN
Malnutrition is a highly prevalent complication in patients with traumatic brain injury (TBI), and it is closely related to the prognosis of patients. Accurate identification of patients at high risk of malnutrition is essential. Therefore, we analyzed the risk factors of malnutrition in patients with TBI and developed a model to predict the risk of malnutrition. A retrospective collection of 345 patients with TBI, and they were divided into malnutrition and comparison groups according to the occurrence of malnutrition. Univariate correlation and multifactor logistic regression analyses were performed to determine patients' malnutrition risk factors. We used univariate and logistic regression (forward stepwise method) analyses to identify significant predictors associated with malnutrition in patients with TBI and developed a predictive model for malnutrition prediction. The model's discrimination, calibration, and clinical utility were evaluated using the receiver operating characteristic (ROC) curve, calibration plots, and decision curve analysis (DCA). A total of 216 patients (62.6%) developed malnutrition. Multifactorial logistic regression analysis showed that pulmonary infection, urinary tract infection, dysphagia, application of NGT, GCS score ≤ 8, and low ADL score were independent risk factors for malnutrition in patients with TBI (P < 0.05). The area under the curve of the model was 0.947. Calibration plots showed good discrimination of model calibration. DCA showed that the column line plot models were all clinically meaningful when nutritional interventions were performed over a considerable range of threshold probabilities (0-0.98). Malnutrition is widespread in patients with TBI, and the nomogram is a good predictor of whether patients develop malnutrition.
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The study investigates the therapeutic effects and mechanisms of ginsenoside Rg_1(GRg_1) on sepsis-induced acute lung injury(SALI). A murine model of SALI was created using cecal ligation and puncture(CLP) surgery, and mice were randomly assigned to groups for GRg_1 intervention. Survival and body weight changes were recorded, lung function was assessed with a non-invasive lung function test system, and lung tissue damage was evaluated through HE staining. The content and expression of inflammatory factors were measured by ELISA and qRT-PCR. Apoptosis was examined using flow cytometry and TUNEL staining. The activation and expression of apoptosis-related molecules cysteinyl aspartate specific proteinase 3(caspase-3), B-cell lymphoma-2(Bcl-2), Bcl-2 associated X protein(Bax), and endoplasmic reticulum stress-related molecules protein kinase R-like endoplasmic reticulum kinase(PERK), eukaryotic initiation factor 2α(eIF2α), activating transcription factor 4(ATF4), and C/EBP homologous protein(CHOP) were studied using Western blot and qRT-PCR. In addition, an in vitro model of lipopolysaccharide(LPS)-induced lung alveolar epithelial cell injury was used, with the application of the endoplasmic reticulum stress inducer tunicamycin to validate the action mechanism of GRg_1. RESULTS:: indicated that, when compared to the model group, GRg_1 intervention significantly enhanced the survival time of CLP mice, mitigated body weight loss, and improved impaired lung function indices. The GRg_1-treated mice also displayed reduced lung tissue pathological scores, a reduced lung tissue wet-to-dry weight ratio, and lower protein content in the bronchoalveolar lavage fluid. Serum levels of interleukin-6(IL-6), interleukin-1ß(IL-1ß), and tumor necrosis factor-α(TNF-α), as well as the mRNA expressions of these cytokines in lung tissues, were decreased. There was a notable decrease in the proportion of apopto-tic alveolar epithelial cells, and down-regulated expressions of caspase-3, Bax, PERK, eIF2α, ATF4, and CHOP and up-regulated expression of Bcl-2 were observed. In vitro findings showed that the apoptosis-lowering and apoptosis-related protein down-regulating effects of GRg_1 were significantly inhibited with the co-application of tunicamycin. Altogether, GRg_1 reduces apoptosis of alveolar epithelial cells, inhibits inflammation in the lungs, alleviates lung injury, and enhances lung function, possibly through the PERK/eIF2α/ATF4/CHOP pathway.
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Factor de Transcripción Activador 4 , Lesión Pulmonar Aguda , Células Epiteliales Alveolares , Apoptosis , Factor 2 Eucariótico de Iniciación , Ginsenósidos , Sepsis , Factor de Transcripción CHOP , eIF-2 Quinasa , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/genética , Ginsenósidos/farmacología , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Ratones , Apoptosis/efectos de los fármacos , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción CHOP/genética , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/genética , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Factor 2 Eucariótico de Iniciación/genética , Masculino , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Humanos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Organic piezochromic materials that manifest pressure-stimuli-responses are important in various fields such as data storage and anticounterfeiting. The manipulation of piezofluorochromic behaviors for these materials is promising but remains a great challenge. Herein, a non-luminous components regulated strategy is developed and organic molecular cages (OMCs), a burgeoning class of crystalline organic materials with structural dynamics, are first explored for the design of piezofluorochromic materials with tunable luminescence. A series of OMCs based on aggregation-induced emission (AIE) chromophores, termed Cageâ 1-3, are synthesized and their piezofluorochromic behaviors are investigated by diamond anvil cell technique. Due to the sufficient voids between its flexible chromophores offered by the OMC structure, Cageâ 1 exhibits thermofluorochromic and piezofluorochromic properties. Moreover, the piezofluorochromic performance of this OMC could be further promoted by replacing its non-luminous components with improved flexibilities, and a remarkable luminescence peak shift by 150â nm together with a response sensitivity of 13.8â nm GPa-1 was achieved upon hydrostatic compression. The cage structure plays a vital role in facilitating efficient and reversible piezofluorochromic behaviors. This study has shed light on the rational design and exploitation of OMCs as an exceptional platform to accomplish customizable piezofluorochromic behaviors and enlarge their potential applications in pressure-based luminescence.
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The rational design and construction of hydrogen-bonded organic frameworks (HOFs) are crucial for enabling their practical applications, but controlling their structure and preparation as intended remains challenging. Inspired by reticular chemistry, two novel blue-emitting NKM-HOF-1 and NKM-HOF-2 were successfully constructed based on two judiciously designed peripherally extended pentiptycene carboxylic acids, namely H8PEP-OBu and H8PEP-OMe, respectively. The large pores within these two HOFs can adsorb fluorescent molecules such as diketopyrrolopyrrole (DPP) and 9-anthraldehyde (AnC) to form HOFs â DPP/AnC composites, subsequently used in the fabrication of white-light-emitting devices (WLEDs). Specifically, two WLEDs were assembled by coating NKM-HOF-1 â DPP-0.13/AnC-3.5 and NKM-HOF-2 â DPP-0.12/AnC-3 on a 330 nm ultraviolet LED bulb, respectively. The corresponding CIE coordinates were (0.29, 0.33) and (0.32, 0.34), along with corresponding color temperatures of 7815 K and 6073 K. This work effectively demonstrates the feasibility of employing reticular chemistry strategies to predict and design HOFs with specific topologies for targeted applications.
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Mitochondrial transfer occurs between cells, and it is important for damaged cells to receive healthy mitochondria to maintain their normal function and protect against cell death. Accumulating evidence suggests that the functional mitochondria of astrocytes are released and transferred to oxygen-glucose deprivation/reoxygenation (OGD/R)-injured neurons. Mild hypothermia (33 °C) is capable of promoting this process, which partially restores the function of damaged neurons. However, the pathways and mechanisms by which mild hypothermia facilitates mitochondrial transfer remain unclear. We are committed to studying the role of mild hypothermia in neuroprotection to provide reliable evidences and insights for the clinical application of mild hypothermia in brain protection. Tunneling nanotubes (TNTs) are considered to be one of the routes through which mitochondria are transferred between cells. In this study, an OGD/R-injured neuronal model was successfully established, and TNTs, mitochondria, neurons and astrocytes were double labeled using immunofluorescent probes. Our results showed that TNTs were present and involved in the transfer of mitochondria between cells in the mixed-culture system of neurons and astrocytes. When neurons were subjected to OGD/R exposure, TNT formation and mitochondrial transportation from astrocytes to injured neurons were facilitated. Further analysis revealed that mild hypothermia increased the quantity of astrocytic mitochondria transferred into damaged neurons through TNTs, raised the mitochondrial membrane potential (MMP), and decreased the neuronal damage and death during OGD/R. Altogether, our data indicate that TNTs play an important role in the endogenous neuroprotection of astrocytic mitochondrial transfer. Furthermore, mild hypothermia enhances astrocytic mitochondrial transfer into OGD/R-injured neurons via TNTs, thereby promoting neuroprotection and neuronal recovery.
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Estructuras de la Membrana Celular , Hipotermia , Nanotubos , Oxígeno , Humanos , Oxígeno/metabolismo , Glucosa/metabolismo , Astrocitos/metabolismo , Hipotermia/metabolismo , Células Cultivadas , Neuronas/metabolismo , Mitocondrias/metabolismoRESUMEN
AIMS: Neurogenic bladder (NB) is a prevalent and debilitating consequence of spinal cord injury (SCI). Indeed, the accurate prognostication of early bladder outcomes is crucial for patient counseling, rehabilitation goal setting, and personalized intervention planning. METHODS: A retrospective exploratory analysis was conducted on a cohort of consecutive SCI patients admitted to a rehabilitation facility in China from May 2016 to December 2022. Demographic, clinical, and electrophysiological data were collected within 40 days post-SCI, with bladder outcomes assessed at 3 months following SCI onset. RESULTS: The present study enrolled 202 SCI patients with a mean age of 40.3 ± 12.3 years. At 3 months post-SCI, 79 participants exhibited complete bladder emptying. Least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analyses identified the H-reflex of the soleus muscle, the American Spinal Injury Association Lower Extremity Motor Score (ASIA-LEMS), and the time from lesion to rehabilitation facility (TLRF) as significant independent predictors for bladder emptying. A scoring system named HALT was developed, yielding a strong discriminatory performance with an area under the receiver operating characteristics curve (aROC) of 0.878 (95% CI: 0.823-0.933). A simplified model utilizing only the H-reflex exhibited excellent discriminatory ability with an aROC of 0.824 (95% CI: 0.766-0.881). Both models demonstrated good calibration via the Hosmer-Lemeshow test and favorable clinical net benefits through decision curve analysis (DCA). In comparison to ASIA-LEMS, both the HALT score and H-reflex showed superior predictive accuracy for bladder outcome. Notably, in individuals with incomplete injuries, the HALT score (aROC = 0.973, 95% CI: 0.940-1.000) and the H-reflex (aROC = 0.888, 95% CI: 0.807-0.970) displayed enhanced performance. CONCLUSION: Two reliable models, the HALT score and the H-reflex, were developed to predict bladder outcomes as early as 3 months after SCI onset. Importantly, this study provides hitherto undocumented evidence regarding the predictive significance of the soleus H-reflex in relation to bladder outcomes in SCI patients.
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Traumatismos de la Médula Espinal , Vejiga Urinaria , Humanos , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Traumatismos de la Médula Espinal/diagnóstico , Traumatismos de la Médula Espinal/terapia , Músculo Esquelético , Curva ROCRESUMEN
While surface-enhanced Raman spectroscopy (SERS) has experienced substantial advancements since its discovery in the 1970s, it is an opportunity to celebrate achievements, consider ongoing endeavors, and anticipate the future trajectory of SERS. In this perspective, we encapsulate the latest breakthroughs in comprehending the electromagnetic enhancement mechanisms of SERS, and revisit CT mechanisms of semiconductors. We then summarize the strategies to improve sensitivity, selectivity, and reliability. After addressing experimental advancements, we comprehensively survey the progress on spectrum-structure correlation of SERS showcasing their important role in promoting SERS development. Finally, we anticipate forthcoming directions and opportunities, especially in deepening our insights into chemical or biological processes and establishing a clear spectrum-structure correlation.
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The present study aimed to establish an effective prognostic nomogram model based on the Naples prognostic score (NPS) for resectable thoracic esophageal squamous cell carcinoma (ESCC). A total of 277 patients with ESCC, who underwent standard curative esophagectomy and designated as study cohort, were retrospectively analyzed. The patients were divided into different groups, including NPS 0, NPS 1, NPS 2, and NPS 3 or 4 groups, for further analysis, and the results were validated in an external cohort of 122 ESCC patients, who underwent surgery at another cancer center. In our multivariate analysis of the study cohort showed that the tumor-node-metastasis (TNM) stage, systemic inflammation score, and NPS were the independent prognostic factors for the overall survival (OS) and progression-free survival (PFS) durations. In addition, the differential grade was also an independent prognostic factor for the OS in the patients with ESCC after surgery (all Pâ <â .05). The area under the curve of receiver operator characteristics for the PFS and OS prediction with systemic inflammation score and NPS were 0.735 (95% confidence interval [CI] 0.676-0.795, Pâ <â .001) and 0.835 (95% CI 0.786-0.884, Pâ <â .001), and 0.734 (95% CI 0.675-0.793, Pâ <â .001) and 0.851 (95% CI 0.805-0.896, Pâ <â .001), respectively. The above independent predictors for OS or PFS were all selected in the nomogram model. The concordance indices (C-indices) of the nomogram models for predicting OS and PFS were 0.718 (95% CI 0.681-0.755) and 0.669 (95% CI 0.633-0.705), respectively, which were higher than that of the 7th edition of American Joint Committee on Cancer TNM staging system [C-index 0.598 (95% CI 0.558-0.638) for OS and 0.586 (95% CI 0.546-0.626) for PFS]. The calibration curves for predicting the 5-year OS or PFS showed a good agreement between the prediction by nomogram and actual observation. In the external validation cohort, the nomogram discrimination for OS was better than that of the 7th edition of TNM staging systems [C-index: 0.697 (95% CI 0.639-0.755) vs 0.644 (95% CI 0.589-0.699)]. The calibration curves showed good consistency in predicting the 5-year survival between the actual observation and nomogram predictions. The decision curve also showed a higher potential of the clinical application of predicting the 5-years OS of the proposed nomogram model as compared to that of the 7th edition of TNM staging systems. The preoperative NPS-based nomogram model had a certain potential role for predicting the prognosis of ESCC patients.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Esofagectomía , Nomogramas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Persona de Mediana Edad , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Pronóstico , Esofagectomía/métodos , Anciano , Estadificación de Neoplasias , AdultoRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related mortality and is characterised by extensive invasive and metastatic potential. Previous studies have shown that vitexicarpin extracted from the fruits of Vitex rotundifolia can impede tumour progression. However, the molecular mechanisms involved in CRC treatment are still not fully established. PURPOSE: Our study aimed to investigate the anticancer activity, targets, and molecular mechanisms of vitexicarpin in CRC hoping to provide novel therapies for patients with CRC. STUDY DESIGN/METHODS: The impact of vitexicarpin on CRC was assessed through various experiments including MTT, clone formation, EDU, cell cycle, and apoptosis assays, as well as a tumour xenograft model. CETSA, label-free quantitative proteomics, and Biacore were used to identify the vitexicarpin targets. WB, Co-IP, Ubiquitination assay, IF, molecular docking, MST, and cell transfection were used to investigate the mechanism of action of vitexicarpin in CRC cells. Furthermore, we analysed the expression patterns and correlation of target proteins in TCGA and GEPIA datasets and clinical samples. Finally, wound healing, Transwell, tail vein injection model, and tissue section staining were used to demonstrate the antimetastatic effect of vitexicarpin on CRC in vitro and in vivo. RESULTS: Our findings demonstrated that vitexicarpin exhibits anticancer activity by directly binding to inosine monophosphate dehydrogenase 2 (IMPDH2) and that it promotes c-Myc ubiquitination by disrupting the interaction between IMPDH2 and c-Myc, leading to epithelial-mesenchymal transition (EMT) inhibition. Vitexicarpin hinders the migration and invasion of CRC cells by reversing EMT both in vitro and in vivo. Additionally, these results were validated by the overexpression and knockdown of IMPDH2 in CRC cells. CONCLUSION: These results demonstrated that vitexicarpin regulates the interaction between IMPDH2 and c-Myc to inhibit CRC proliferation and metastasis both in vitro and in vivo. These discoveries introduce potential molecular targets for CRC treatment and shed light on new mechanisms for c-Myc regulation in tumours.
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Neoplasias Colorrectales , Flavonoides , Ubiquitinación , Vitex , Animales , Humanos , Masculino , Ratones , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , IMP Deshidrogenasa/metabolismo , IMP Deshidrogenasa/antagonistas & inhibidores , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ubiquitinación/efectos de los fármacos , Vitex/química , Ensayos Antitumor por Modelo de Xenoinjerto , Flavonoides/farmacologíaRESUMEN
Cyclic dinucleotides (CDNs) are cyclic molecules consisting of two nucleoside monophosphates linked by two phosphodiester bonds, which act as a second messenger and bind to the interferon gene stimulating factor (STING) to activate the downstream signaling pathway and ultimately induce interferon secretion, initiating an anti-infective immune response. Cyclic dinucleotides and their analogs are lead compounds in the immunotherapy of infectious diseases and tumors, as well as immune adjuvants with promising applications. Many agonists of pathogen recognition receptors have been developed as effective adjuvants to optimize vaccine immunogenicity and efficacy. In this work, the binding mechanism of human-derived interferon gene-stimulating protein and its isoforms with cyclic dinucleotides and their analogs was theoretically investigated using computer simulations and combined with experimental results in the hope of providing guidance for the subsequent synthesis of cyclic dinucleotide analogs.