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Elton's biotic resistance hypothesis posits that species-rich communities are more resistant to invasion. However, it remains unknown how species, phylogenetic and functional richness, along with environmental and human-impact factors, collectively affect plant invasion as alien species progress along the introduction-naturalization-invasion continuum. Using data from 12,056 local plant communities of the Czech Republic, this study reveals varying effects of these factors on the presence and richness of alien species at different invasion stages, highlighting the complexity of the invasion process. Specifically, we demonstrate that although species richness and functional richness of resident communities had mostly negative effects on alien species presence and richness, the strength and sometimes also direction of these effects varied along the continuum. Our study not only underscores that evidence for or against Elton's biotic resistance hypothesis may be stage-dependent but also suggests that other invasion hypotheses should be carefully revisited given their potential stage-dependent nature.
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Dogs interact with humans effectively and intimately. However, the neural underpinnings for such interspecies social communication are not understood. It is known that interbrain activity coupling, i.e., the synchronization of neural activity between individuals, represents the neural basis of social interactions. Here, previously unknown cross-species interbrain activity coupling in interacting human-dog dyads is reported. By analyzing electroencephalography signals from both dogs and humans, it is found that mutual gaze and petting induce interbrain synchronization in the frontal and parietal regions of the human-dog dyads, respectively. The strength of the synchronization increases with growing familiarity of the human-dog dyad over five days, and the information flow analysis suggests that the human is the leader while the dog is the follower during human-dog interactions. Furthermore, dogs with Shank3 mutations, which represent a promising complementary animal model of autism spectrum disorders (ASD), show a loss of interbrain coupling and reduced attention during human-dog interactions. Such abnormalities are rescued by the psychedelic lysergic acid diethylamide (LSD). The results reveal previously unknown interbrain synchronizations within an interacting human-dog dyad which may underlie the interspecies communication, and suggest a potential of LSD for the amelioration of social impairment in patients with ASD.
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The aim of this study was to investigate the effects of immersion on immune enzyme activity, haemolymph index, intestinal microbiome and metabolome of E. sinensis after low temperature air exposure. The results showed that low temperature air exposure induced stress response, which led to hepatopancreas injury and increased membrane permeability, but this situation was reversible and alleviated after immersion. In addition, after exposure to low temperature air, haemolymph metabolism-related substances such as glucose and total cholesterol were significantly different from the initial value (P < 0.05), and gradually returned to the initial level after immersion. The changes of intestinal flora and hepatopancreas metabolism caused by low temperature air exposure did not fully recover after immersion, and its negative effects did not completely disappear. The sequencing results showed that the species composition and diversity of intestinal microorganisms of Chinese mitten crabs were changed after low temperature air exposure and immersion treatment. The relative abundance of Bacteroidetes and Proteobacteria were increased, while the relative abundance of Firmicutes was decreased (P < 0.05). Metabolomics analysis showed that lysine levels increased significantly, taurocholic acid levels decreased significantly, and amino acid metabolism and lipid metabolism balance were disturbed in hepatopancreas of E. sinensis after exposure to low temperature air and immersion (P < 0.05). This study will provide new insights into the recovery mechanism of water immersion on Chinese mitten crabs after exposure to air.
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RATIONALE AND OBJECTIVES: To investigate the predictive value of coronary CT angiography (CCTA)-based radiomics for vessel-specific ischemia by stress dynamic CT myocardial perfusion imaging (MPI). MATERIALS AND METHODS: Patients with typical angina/atypical angina/non-angina chest pain who underwent both stress dynamic CT MPI and CCTA scans were retrospectively enrolled. The following models were constructed for ischemic prediction using logistic regression and CCTA-derived quantitative and radiomic features: plaque quantitative model, lumen quantitative model, CT-fractional flow reserve (CT-FFR) model, integrative quantitative model, plaque radiomic model, peri-coronary adipose tissue (pCAT) radiomic model, integrative radiomic model, and quantitative and radiomic fusion model. A relative myocardial blood flow ≤ 0.75 on stress dynamic CT MPI was considered ischemic. The models' performances were quantified by the area under the receiver-operating characteristic curve (AUC). RESULTS: 386 coronary vessels (stenosis grade: 25%â¼75%; training set: 200 [ischemia/non-ischemia=96/104]; test set:186 [ischemia/non-ischemia=79/107]) from 326 patients were included. The plaque radiomic model (training/test set: AUC=0.81/0.80) outperformed (p < .05) both the plaque quantitative (training/test set: AUC=0.71/0.68) model and the lumen quantitative (training/test set: AUC=0.69/0.65) model in identifying ischemia. The integrative radiomic model (training/test set: AUC=0.83/0.82) outperformed (p < .05) the CT-FFR model (training/test set: AUC=0.74/0.73) for ischemic prediction. The quantitative and radiomic fusion model (training/test set: AUC=0.86/0.84) outperformed (p < .05) the integrative quantitative model (training/test set: AUC=0.79/0.77) for ischemic detection. CONCLUSION: The plaque and pCAT radiomic features were superior to the plaque and pCAT quantitative features in predicting ischemia and the addition of the radiomic features to the quantitative features for ischemic identification yielded incremental discriminatory value.
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OBJECTIVES: To evaluate the (1) successful surgery proportion in patients with clear structural lesions on MRI and single abnormality on 18F-fluorodeoxyglucose positron emission tomography/Magnetic resonance imaging (18F-FDG PET/MRI); (2) predictive value of 18F-FDG PET/MRI for postsurgical outcome in refractory epilepsy patients. METHODS: A retrospective study was conducted on 123 patients diagnosed with refractory epilepsy who underwent presurgical evaluation involving 18F-FDG PET/MRI and were followed for one-year post-surgery. Two neuroradiologists interpreted the PET/MRI images using visual analysis and an asymmetry index based on the standard uptake value. The Engel classification was used to assess surgical outcomes one-year post-surgery. Prognostic factors predicting post-surgical seizure outcomes were explored using univariate and binary logistic regression. RESULTS: Definitely single lesion abnormality was observed in 35.0% (43/123) of the patients on the MRI portion of PET/MRI. The proportion increased to 74.0% (91/123) when 18 F-FDG PET portion was added. About 75% (69/91) of patients displaying a clear-cut lesion on 18 F-FDG PET/MRI were classified as Engel Class I one-year post-surgery. The proportion of Engel Class I patients was not significantly different when comparing MRI-single lesion patients with MRI-negative, PET-single lesion patients one year after surgery (81.4% vs. 70.0%, P = 0.24). Binary logistic regression analysis revealed that the detection of a clear single lesion on 18 F-FDG PET/MRI was a strong positive predictor of a favorable surgical outcome (OR 3.518, 95% CI 1.363-9.077, p = 0.009). CONCLUSION: Single lesion detected on 18 F-FDG PET/MRI is useful to predict good surgical outcome for refractory epilepsy patients; Those patients should be considered as candidates for surgery.
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Aggregation-induced emission (AIE)allows tunable photoluminescence via the simple regulation of molecular aggregation. The research spurt along this vein has also offered tremendous opportunities for light-responsive artificial molecular machines that are to be fully explored for performing versatile functions. Herein, the study reports a light-driven Feringa-type motor, when in the appropriate aggregation state, not only demonstrates the light-activated rotary motion but emits photons with good quantum yield. A semi-quantitative TD-DFT calculation is also conducted to aid the understanding of the competitive photoluminescence and photoisomerization processes of the motor. Cytotoxicity test shows this motor possesses good biocompatibility, laying a solid foundation for applying it in the bio-environment. The results demonstrated that the engagement of the aggregation-induced emission concept and light-driven Feringa-motor can lead to the discovery of the novel motorized AIEgen, which will further stimulate the rise of more advanced molecular motors capable of executing multi-functionalities.
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The endoplasmic reticulum (ER) is crucial for maintaining cell homeostasis because it is the primary site for synthesizing secreted and transmembrane proteins and lipids. The unfolded protein response (UPR) is activated to restore ER homeostasis under ER stress. However, the relationship between lipids and the ER stress response in plants is not well understood. Arabidopsis Golgi anti-apoptotic proteins (GAAPs) are involved in resisting ER stress. To elucidate the function of GAAPs, PASTICCINO2 (PAS2), involved in very long-chain fatty acid (VLCFA) synthesis, was found to interact with GAAPs and IRE1. Single pas2 and gaap1/gaap2pas2 double mutants exhibited increased seedling damage and impaired UPR response under chronic ER stress. Site mutation combined with genetic analysis revealed that the role of PAS2 in resisting ER stress depended on its VLCFA synthesis domain. VLCFA contents were upregulated under ER stress, which required GAAPs. Exogenous VLCFAs partially restored the defect in UPR upregulation caused by PAS2 or GAAP mutations under chronic ER stress. These findings demonstrate that the association of PAS2 with GAAPs confers plant resistance to ER stress by regulating VLCFA synthesis and the UPR. This provides a basis for further studies on the connection between lipids and cell fate decisions under stress.
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Background: Quantitative flow ratio (QFR) is a novel diagnostic modality for the functional testing of coronary artery stenosis, but evidence concerning the postoperative prognostic implication of QFR in noncardiac surgery (NCS) of patients with coronary artery disease (CAD) is limited. The purpose of this study was to examine the role of QFR in perioperative risk prediction in patients with coronary heart disease. Methods: This retrospective cohort study was conducted in The First Affiliated Hospital of Wenzhou Medical University between 2013 and 2022, and consecutively included patients with CAD who had undergone NCS <1 year after coronary angiography. The primary endpoint was major adverse cardiovascular events (MACEs), which were defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, cardiopulmonary arrest, malignant ventricular arrhythmia (MVA), congestive heart failure, and revascularization. Univariate and multifactorial Cox regression was used to identify the independent risk factors for perioperative cardiovascular events and to construct new models. The area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to compare the newly constructed model with existing traditional models. Results: Among the 929 participants enrolled (median age 68 years; 72.0% male), the primary endpoint was met in 67 (7.2%) patients within 30 days of follow-up. There was no significant difference in the incidence of the primary endpoint between patients with QFR <0.75 and those with "gray zone" lesions (0.75≤ QFR ≤0.8) (log-rank P=0.325). Patients with QFR <0.75 and those with "gray zone" lesions (0.75≤ QFR ≤0.8) had a higher incidence of primary endpoint events compared to patients with QFR >0.8. [QFR <0.75 vs. QFR >0.8: adjusted hazard ratio (HR) =20.70, P<0.001; 0.75≤ QFR ≤0.8 vs. QFR >0.8: HR =15.99, P<0.001]. The independent predictors of MACEs events within 30 days after NCS were albumin level [HR =0.92, 95% confidence interval (CI): 0.87-0.98; P=0.008], emergency surgery (HR =4.12, 95% CI: 1.66-10.23; P=0.002), and QFR ≤0.8 (HR =15.92, 95% CI: 5.96-42.51; P<0.001). In addition, adjusting the original Revised Cardiac Risk Index (RCRI) with QFR ≤0.8 as a risk factor significantly improved the risk stratification of postoperative adverse events, with the adjusted AUC rising from 0.574 to 0.740 (P<0.001). Conclusions: QFR ≤0.8 could independently predict perioperative cardiovascular adverse events in patients with CAD undergoing NCS and improve the predictive value of original predictive index. Gray-zone lesions (0.75≤ QFR ≤0.8) should be actively treated.
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BACKGROUND AND AIMS: High-density lipoprotein (HDL) might lose atheroprotective functions in the presence of diabetes. We sought to examine associations of HDL cholesterol (HDL-C) and HDL particle (HDL-P) subclasses with risk of coronary heart disease (CHD) stratified by diabetes. METHODS: We included 393,516 participants (20,691 diabetics and 372,825 nondiabetics) from the UK Biobank. Restricted cubic splines cooperated with Cox model were used to estimate associations of HDL with CHD. RESULTS: During a median follow-up of 13.0 years, 3398 (16.4 %) and 24,772 (6.6 %) incident CHD events occurred among diabetics and nondiabetics, respectively. HDL-C showed inverse associations with CHD among nondiabetics, whereas U-shaped associations among diabetics. Compared to individuals with normal HDL-C (40th - 60th percentile, 1.32-1.51 mmol/L), those in the top percentile (95th, >2.16 mmol/L) had lower CHD risks among nondiabetics (Hazard Ratio, 0.79; 95 % confidence interval, 0.73-0.86), but higher risks among diabetics (1.38, 1.02-1.88). As for HDL-P, there were inverted U-shaped associations of very large HDL-P and linearly negative associations of large HDL-P with CHD among nondiabetics; however, linearly positive associations of very large HDL-P and null associations of large HDL were observed among diabetics. L-shaped associations of medium and small HDL-P were found both in diabetics and nondiabetics. CONCLUSIONS: Very high HDL-C levels were associated with lower CHD risks in nondiabetics, but higher risks in diabetics. Smaller HDL-P was negatively, whereas very large HDL-P was positively associated with CHD risk in diabetics. These data advance our knowledge about the interactions between HDL and diabetes.
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OBJECTIVE: The right upper transversal hepatectomy (RUTH) is considered a complex technique of parenchymal-sparing hepatectomies. The intraoperative management of the right hepatic vein (RHV) is still controversial because it may cause obstruction of outflow in the remnant hepatic segment. The aim of this study is to present our experience of laparoscopic RUTH and the strategy of RHV resection and reconstruction in different settings. METHODS: Five patients who underwent laparoscopic RUTH for liver tumor were enrolled retrospectively. Clinical and pathological features of the patients, peri-operative treatment, as well as short- and long-term outcomes were collected for analysis. RESULTS: Laparoscopic RUTH was successfully performed in all five patients. Two individuals underwent RUTH while preserving RHV. Among the remaining patients who underwent RUTH with RHV resection, one patient underwent RHV reconstruction but the others did not. Immediate or long-term venous related complications did not occurred in a median follow-up period of nine months. CONCLUSIONS: Laparoscopic RUTH surgery for tumors in the right upper region of the liver is safe and feasible. The strategic workflow we proposed for the resection and reconstruction of the RHV offers a reliable method for preserving liver parenchyma and reducing the risk of postoperative liver failure.
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INTRODUCTION: There remains a critical need for precise localization of the epileptogenic foci in individuals with drug-resistant epilepsy (DRE). 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging can reveal hypometabolic regions during the interval between seizures in patients with epilepsy. However, visual-based qualitative analysis is time-consuming and strongly influenced by physician experience. CortexID Suite is a quantitative analysis software that helps to evaluate PET imaging of the human brain. Therefore, we aimed to evaluate the efficacy of CortexID quantitative analysis in the localization of the epileptogenic zone in patients with temporal lobe epilepsy (TLE). METHODS: A total of 102 patients with epilepsy who underwent 18F-FDG-PET examinations were included in this retrospective study. The PET visual analysis was interpreted by two nuclear medicine physicians, and the quantitative analysis was performed automatically using CortexID analysis software. The assumed epileptogenic zone was evaluated comprehensively by two skilled neurologists in the preoperative assessment of epilepsy. The accuracy of epileptogenic zone localization in PET visual analysis was compared with that in CortexID quantitative analysis. RESULTS: The diagnostic threshold for the difference in the metabolic Z-score between the right and left sides of medial temporal lobe epilepsy (MTLE) was calculated as 0.87, and that for lateral temporal lobe epilepsy (LTLE) was 2.175. In patients with MTLE, the area under the curve (AUC) was 0.922 for PET visual analysis, 0.853 for CortexID quantitative analysis, and 0.971 for the combined diagnosis. In patients with LTLE, the AUC was 0.842 for PET visual analysis, 0.831 for CortexID quantitative analysis, and 0.897 for the combined diagnosis. These results indicate that the diagnostic efficacy of CortexID quantitative analysis is not inferior to PET visual analysis (p > 0.05), while combined analysis significantly increases diagnostic efficacy (p < 0.05). Among the 23 patients who underwent surgery, the sensitivity and specificity of PET visual analysis for localization were 95.4% and 66.7%, and the sensitivity and specificity of CortexID quantitative analysis were 100% and 50%. CONCLUSION: The diagnostic efficacy of CortexID quantitative analysis is comparable to PET visual analysis in the localization of the epileptogenic zone in patients with TLE. CortexID quantitative analysis combined with visual analysis can further improve the accuracy of epileptogenic zone localization.
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Intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis, and elucidation of the molecular mechanisms underlying iCCA malignancy is of great significance. Glycosylation, an important post-translational modification, is closely associated with tumor progression. Altered glycosylation, including aberrant sialylation resulting from abnormal expression of sialyltransferases (STs) and neuraminidases (NEUs), is a significant feature of cancer cells. However, there is limited information on the roles of STs and NEUs in iCCA malignancy. Here, utilizing our proteogenomic resources from a cohort of 262 patients with iCCA, we identified ST3GAL1 as a prognostically relevant molecule in iCCA. Moreover, overexpression of ST3GAL1 promoted proliferation, migration, and invasion and inhibited apoptosis of iCCA cells in vitro. Through proteomic analyses, we identified the downstream pathway potentially regulated by ST3GAL1, which was the NF-κB signaling pathway, and further demonstrated that this pathway was positively correlated with malignancy in iCCA cells. Notably, glycoproteomics showed that O-glycosylation was changed in iCCA cells with high ST3GAL1 expression. Importantly, the altered O-glycopeptides underscored the potential utility of O-glycosylation profiling as a discriminatory marker for iCCA cells with ST3GAL1 overexpression. Additionally, miR-320b was identified as a post-transcriptional regulator of ST3GAL1, capable of suppressing ST3GAL1 expression and then reducing the proliferation, migration, and invasion abilities of iCCA cell lines. Taken together, these results suggest ST3GAL1 could serve as a promising therapeutic target for iCCA.
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Brain PET imaging often faces challenges from head motion (HM), which can introduce artifacts and reduce image resolution, crucial in clinical settings for accurate treatment planning, diagnosis, and monitoring. United Imaging Healthcare has developed NeuroFocus, an HM correction (HMC) algorithm for the uMI Panorama PET/CT system, using a data-driven, statistics-based approach. The HMC algorithm automatically detects HM using a centroid-of-distribution technique, requiring no parameter adjustments. This study aimed to validate NeuroFocus and assess the prevalence of HM in clinical short-duration 18F-FDG scans. Methods: The study involved 317 patients undergoing brain PET scans, divided into 2 groups: 15 for HMC validation and 302 for evaluation. Validation involved patients undergoing 2 consecutive 3-min single-bed-position brain 18F-FDG scans-one with instructions to remain still and another with instructions to move substantially. The evaluation examined 302 clinical single-bed-position brain scans for patients with various neurologic diagnoses. Motion was categorized as small or large on the basis of a 5% SUV change in the frontal lobe after HMC. Percentage differences in SUVmean were reported across 11 brain regions. Results: The validation group displayed a large negative difference (-10.1%), with variation of 5.2% between no-HM and HM scans. After HMC, this difference decreased dramatically (-0.8%), with less variation (3.2%), indicating effective HMC application. In the evaluation group, 38 of 302 patients experienced large HM, showing a 10.9% ± 8.9% SUV increase after HMC, whereas most exhibited minimal uptake changes (0.1% ± 1.3%). The HMC algorithm not only enhanced the image resolution and contrast but also aided in disease identification and reduced the need for repeat scans, potentially optimizing clinical workflows. Conclusion: The study confirmed the effectiveness of NeuroFocus in managing HM in short clinical 18F-FDG studies on the uMI Panorama PET/CT system. It found that approximately 12% of scans required HMC, establishing HMC as a reliable tool for clinical brain 18F-FDG studies.
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Algoritmos , Encéfalo , Procesamiento de Imagen Asistido por Computador , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Procesamiento de Imagen Asistido por Computador/métodos , Encéfalo/diagnóstico por imagen , Adulto , Fluorodesoxiglucosa F18 , Artefactos , Cabeza/diagnóstico por imagen , Anciano de 80 o más Años , Adulto JovenRESUMEN
Ginger polysaccharides (GP) promote growth and development in fish. However, the effects of GP on crucian carp remain unclear. The present study investigated the effects of GP on the growth performance, immunity, intestinal microbiota, and disease resistance in crucian carp. Four treatment groups were established with different concentrations of GP (0.1 %, 0.2 %, 0.4 %, and 0.8 %). GP was not added as the control group, and the feeding period lasted for 56 d, followed by a 96-h anti-infection treatment using Aeromonas hydrophila. The results showed that dietary GP significantly improved growth performance, especially in the 0.4 % GP group. Furthermore, GP administration notably increased serum lysozyme (LMZ) activity, digestive enzyme performance, and antioxidant capacity of crucian carp. Moreover, dietary inclusion of GP up-regulated the expression of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), interferon-γ (IFN-γ), and nuclear factor kappa-B (NF-κB) genes while down-regulating IL-10 and transforming growth factor-ß (TGF-ß) gene expressions, thus promoting liver health in crucian carp. Additionally, incorporating GP into the diet regulated both the diversity and composition of the intestinal microbiota in crucian carp, explicitly enhancing the relative abundance of beneficial bacteria, such as Fusobacteriota and Firmicutes. Therefore, GP reduces the mortality of crucian carp infected with A. hydrophila. In conclusion, this study provides novel insights into the application of dietary GP in cultured fish and evaluates the value of traditional Chinese medicinal polysaccharides against pathogenic bacteria.
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Aeromonas hydrophila , Antioxidantes , Carpas , Resistencia a la Enfermedad , Enfermedades de los Peces , Microbioma Gastrointestinal , Polisacáridos , Zingiber officinale , Animales , Aeromonas hydrophila/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Polisacáridos/farmacología , Polisacáridos/química , Resistencia a la Enfermedad/efectos de los fármacos , Antioxidantes/farmacología , Enfermedades de los Peces/microbiología , Enfermedades de los Peces/inmunología , Zingiber officinale/química , Carpas/crecimiento & desarrollo , Carpas/inmunología , Carpas/microbiología , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Suplementos Dietéticos , Alimentación AnimalRESUMEN
Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1-/- but not Trpa1-/- mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1-/- mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons.
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Cadaverina , Ganglios Espinales , Ratones Endogámicos C57BL , Prurito , Canales Catiónicos TRPV , Animales , Prurito/metabolismo , Prurito/inducido químicamente , Canales Catiónicos TRPV/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Masculino , Cadaverina/análogos & derivados , Cadaverina/farmacología , Cadaverina/metabolismo , Ratones , Ratones Noqueados , Humanos , Mastocitos/metabolismo , Mastocitos/efectos de los fármacos , Canal Catiónico TRPA1/metabolismo , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Capsaicina/análogos & derivadosRESUMEN
RATIONALE AND OBJECTIVES: The objective was to assess and examine radiomics models derived from contrast-enhanced CT for their predictive capacity using the sub-regional radiomics regarding the Ki-67 proliferation index (PI) in patients with pathologically confirmed gastrointestinal stromal tumors (GIST). METHODS: In this retrospective study, a total of 412 GIST patients across three institutions (223 from center 1, 106 from center 2, and 83 from center 3) was enrolled. Radiomic features were derived from various sub-regions of the tumor region of interest employing the K-means approach. The Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to identify features correlated with Ki-67 PI level in GIST patients. A support vector machine (SVM) model was then constructed to predict the high level of Ki-67 (Ki-67 index >8%), drawing on the radiomics features from each sub-region within the training cohort. RESULTS: After features selection process, 6, 9, 9, 7 features were obtained to construct SVM models based on sub-region 1, 2, 3 and the entire tumor, respectively. Among different models, the model developed by the sub-region 1 achieved an area under the receiver operating characteristic curve (AUC) of 0.880 (95% confidence interval [CI]: 0.830 to 0.919), 0.852 (95% CI: 0.770-0.914), 0.799 (95% CI: 0.697-0.879) in the training, external test set 1, and 2, respectively. CONCLUSION: The results of the present study suggested that SVM model based on the sub-regional radiomics features had the potential of predicting Ki-67 PI level in patients with GIST.
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GSDMB-mediated pyroptosis facilitates a pro-inflammatory immune microenvironment and needs to be tightly regulated to avoid excessive inflammation. Here, we provide evidence that itaconate and its cell-permeable derivative 4-octyl itaconate (4-OI) can significantly inhibit GSDMB-rendered pyroptotic activity independent of Nrf2. 4-OI interferes proteolytic process of GSDMB by directly modifying Cys54, Cys148 and Ser212 on granzyme A (GrzA), a serine protease that site-specifically cleaves the inter-domain linker of GSDMB, instead of interaction with GSDMB, thereby blocking pyroptosis and exerts anti-inflammatory effects. Moreover, 4-OI alleviates inflammation by suppressing GSDMB-induced pyroptotic cell death during acute colitis models in intestinal epithelial GSDMB conditional transgenic mice. Our data expand the role of 4-OI as a crucial immunometabolic derivative that regulates innate immunity and inflammation through a newly identified posttranslational modification, and targeting of pyroptosis by 4-OI therefore holds potent therapeutic potential for primarily inflammatory and/or autoimmune diseases.
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An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.