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BACKGROUND: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. METHODS: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. RESULTS: A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 159 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). CONCLUSIONS: In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).
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Antihipertensivos , Presión Sanguínea , Servicios Médicos de Urgencia , Hipertensión , Accidente Cerebrovascular , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ambulancias , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/terapia , Tiempo de Tratamiento , Enfermedad Aguda , Estado Funcional , ChinaRESUMEN
Precisely predicting the drug-drug interaction (DDI) is an important application and host research topic in drug discovery, especially for avoiding the adverse effect when using drug combination treatment for patients. Nowadays, machine learning and deep learning methods have achieved great success in DDI prediction. However, we notice that most of the works ignore the importance of the relation type when building the DDI prediction models. In this work, we propose a novel R$^2$-DDI framework, which introduces a relation-aware feature refinement module for drug representation learning. The relation feature is integrated into drug representation and refined in the framework. With the refinement features, we also incorporate the consistency training method to regularize the multi-branch predictions for better generalization. Through extensive experiments and studies, we demonstrate our R$^2$-DDI approach can significantly improve the DDI prediction performance over multiple real-world datasets and settings, and our method shows better generalization ability with the help of the feature refinement design.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Interacciones Farmacológicas , Aprendizaje Automático , Descubrimiento de DrogasRESUMEN
Accurate prediction of drug-target affinity (DTA) is of vital importance in early-stage drug discovery, facilitating the identification of drugs that can effectively interact with specific targets and regulate their activities. While wet experiments remain the most reliable method, they are time-consuming and resource-intensive, resulting in limited data availability that poses challenges for deep learning approaches. Existing methods have primarily focused on developing techniques based on the available DTA data, without adequately addressing the data scarcity issue. To overcome this challenge, we present the Semi-Supervised Multi-task training (SSM) framework for DTA prediction, which incorporates three simple yet highly effective strategies: (1) A multi-task training approach that combines DTA prediction with masked language modeling using paired drug-target data. (2) A semi-supervised training method that leverages large-scale unpaired molecules and proteins to enhance drug and target representations. This approach differs from previous methods that only employed molecules or proteins in pre-training. (3) The integration of a lightweight cross-attention module to improve the interaction between drugs and targets, further enhancing prediction accuracy. Through extensive experiments on benchmark datasets such as BindingDB, DAVIS and KIBA, we demonstrate the superior performance of our framework. Additionally, we conduct case studies on specific drug-target binding activities, virtual screening experiments, drug feature visualizations and real-world applications, all of which showcase the significant potential of our work. In conclusion, our proposed SSM-DTA framework addresses the data limitation challenge in DTA prediction and yields promising results, paving the way for more efficient and accurate drug discovery processes.
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Benchmarking , Descubrimiento de Drogas , Sistemas de Liberación de MedicamentosRESUMEN
Ankyrin-repeat proteins with a suppressor of cytokine signaling box (ASB) proteins belong to the E3 ubiquitin ligase family. 18 ASB members have been identified whose biological functions are mostly unexplored. Here, we discovered that ASB3 was essential for hepatocellular carcinoma (HCC) development and high ASB3 expression predicted poor clinical outcomes. ASB3 silencing induced HCC cell growth arrest and apoptosis in vitro and in vivo. Liver-specific deletion of Asb3 gene suppressed diethylnitrosamine (DEN)-induced liver cancer development. Mechanistically, ASB3 interacted with death receptor 5 (DR5), which promoted ubiquitination and degradation of DR5. We further showed that ASB3 knockdown stabilized DR5 and increased the sensitivity of liver cancer cells to the treatment of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a DR5-dependent manner in cellular and in animal models. In summary, we demonstrated that ASB3 promoted ubiquitination and degradation of DR5 in HCC, suggesting the potential of targeting ASB3 to HCC treatment and overcome TRAIL resistance.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Apoptosis , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Ligandos , Neoplasias Hepáticas/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitinación , HumanosRESUMEN
Short-chain chlorinated aliphatic hydrocarbons (SCAHs), commonly used as industrial reagents and solvents, pose a significant threat to ecosystems and human health as they infiltrate aquatic environments due to extensive usage and accidental spills. Whole-cell biosensors have emerged as cost-effective, rapid, and real-time analytical tools for environmental monitoring and remediation. While the broad ligand specificity of transcriptional factors (TFs) often prohibits the application of such biosensors. Herein, we exploited a semirational transition ligand approach in conjunction with a positive/negative fluorescence-activated cell sorting (FACS) strategy to develop a biosensor based on the TF AlkS, which is highly specific for SCAHs. Furthermore, through promoter-directed evolution, the performance of the biosensor was further enhanced. Mutation in the -10 region of constitutive promoter PalkS resulted in reduced AlkS leakage expression, while mutation in the -10 region of inducible promoter PalkB increased its accessibility to the AlkS-SCAHs complex. This led to an 89% reduction in background fluorescence leakage of the optimized biosensor, M2-463, further enhancing its response to SCAHs. The optimized biosensor was highly sensitive and exhibited a broader dynamic response range with a 150-fold increase in fluorescence output after 1 h of induction. The detection limit (LOD) reached 0.03 ppm, and the average recovery rate of SCAHs in actual water samples ranged from 95.87 to 101.20%. The accuracy and precision of the proposed biosensor were validated using gas chromatography-mass spectrometry (GC-MS), demonstrating the promising application for SCAH detection in an actual environment sample.
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Técnicas Biosensibles , Hidrocarburos Clorados , Técnicas Biosensibles/métodos , Ligandos , Hidrocarburos Clorados/análisis , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Contaminantes Químicos del Agua/análisis , Citometría de Flujo , Regiones Promotoras GenéticasRESUMEN
Performance of the group IV monochalcogenide GeSe in solar cells, electronic, and optoelectronic devices is expected to improve when high-quality single crystalline material is used rather than polycrystalline films. Crystalline flakes represent an attractive alternative to bulk single crystals as their synthesis may be developed to be scalable, faster, and with higher overall yield. However, large - and especially large and thin - single crystal flakes are notoriously hard to synthesize. Here it is demonstrated that vapor-liquid-solid growth combined with direct lateral vapor-solid incorporation produces high-quality single crystalline GeSe ribbons with tens of micrometers size and controllable thickness. Electron microscopy shows that the ribbons exhibit perfect equilibrium (AB) van der Waals stacking order without extended defects across the entire thickness, in contrast to the conventional case of substrate-supported flakes where material is added via layer-by-layer nucleation and growth on the basal plane. Electrical measurements show anisotropic transport and a high Hall mobility of 85 cm2 V-1 s-1, on par with the best single crystals to date. Growth from mixed GeSe and SnSe vapors, finally, yields ribbons with unchanged structure and composition but with jagged edges, promising for applications that rely on ample chemically active edge sites, such as catalysis or photocatalysis.
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Intrahepatic cholangiocarcinoma (ICC) is a high-grade malignant digestive system tumor with an insidious onset and unfavorable prognosis. Liensinine, a small molecule derived from plants, has been proven to have significant tumor suppressor activity in other cancers. However, there are no reports on whether liensinine can inhibit the proliferation or metastasis of ICC. This study aimed to explore the tumor-suppressive activity of liensinine in ICC and its underlying mechanisms. The phenotypic changes in ICC cells were monitored in vitro using cell function tests. Western blot and immunofluorescence analyses verified the efficacy of liensinine. Tumor-bearing nude mice were used to explore the effect of liensinine on tumors and its toxicity and side effects in vivo. Liensinine suppressed ICC cell proliferation and arrested the cell cycle at the G1 phase. The epithelial-mesenchymal transition (EMT) of ICC cells was also inhibited, thereby restraining their invasion and migration of tumor cells. In addition, this study found that the potential mechanism of liensinine inhibiting EMT may be via suppression of the TGF-ß1/P-smad3 signaling pathway through hypoxia-inducible factor 1 alpha (HIF-1a). In vivo experiments showed that liensinine inhibited the growth of Hucc-T1 transplanted tumors in nude mice. Liensinine restrained the proliferation of ICC cells and suppressed EMT in ICC via the HIF-1a-mediated TGF-ß1/P-smad3 signaling pathway.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Isoquinolinas , Fenoles , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Ratones Desnudos , Transducción de Señal , Colangiocarcinoma/metabolismo , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Transición Epitelial-Mesenquimal , Movimiento Celular , Línea Celular TumoralRESUMEN
Well understanding protein function and structure in computational biology helps in the understanding of human beings. To face the limited proteins that are annotated structurally and functionally, the scientific community embraces the self-supervised pre-training methods from large amounts of unlabeled protein sequences for protein embedding learning. However, the protein is usually represented by individual amino acids with limited vocabulary size (e.g. 20 type proteins), without considering the strong local semantics existing in protein sequences. In this work, we propose a novel pre-training modeling approach SPRoBERTa. We first present an unsupervised protein tokenizer to learn protein representations with local fragment pattern. Then, a novel framework for deep pre-training model is introduced to learn protein embeddings. After pre-training, our method can be easily fine-tuned for different protein tasks, including amino acid-level prediction task (e.g. secondary structure prediction), amino acid pair-level prediction task (e.g. contact prediction) and also protein-level prediction task (remote homology prediction, protein function prediction). Experiments show that our approach achieves significant improvements in all tasks and outperforms the previous methods. We also provide detailed ablation studies and analysis for our protein tokenizer and training framework.
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Biología Computacional , Proteínas , Humanos , Proteínas/química , Biología Computacional/métodos , Secuencia de Aminoácidos , Estructura Secundaria de Proteína , AminoácidosRESUMEN
OBJECTIVES: IgG4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory disease. Induction treatment with glucocorticoid (GC) is usually effective, but its tendency of relapse makes the strategy for maintenance treatment a challenge. The WInS IgG4-RD (withdraw immunosuppressants (IMs) and steroid in stable IgG4-RD) trial tested whether discontinuation of GC and IM was feasible in stable IgG4-RD. METHODS: The WInS IgG4-RD trial was a multicentre, open-label, randomised controlled trial. Patients with IgG4-RD receiving GC+IM as maintenance treatment with clinically quiescent disease for at least 12 months were randomised (1:1:1) into three groups: group 1: withdraw GC+IM; group 2: withdraw GC but maintain IM; group 3: maintain GC+IM. The primary outcome was the relapse rate of disease within 18 months. The secondary outcomes included the changes of IgG4-RD Responder Index (RI), Physician's Global Assessment (PGA), serum IgG4 and IgG, as well as adverse events. RESULTS: One hundred and forty-six patients were randomised, with 48 patients in group 1, 49 patients in group 2 and group 3, respectively. Within the 18-month follow-up period, disease relapse occurred in 25 out of 48 (52.1%) patients in group 1 vs 7 out of 49 (14.2%) in group 2 and 6 out of 49 (12.2%) in group 3 (p<0.001). The changes in RI and PGA were significantly higher in group 1 than in group 2 (p<0.001) or group 3 (p<0.001). CONCLUSIONS: The maintenance of IMs, with or without low-dose GC, was found to be superior to withdraw GC+IM in preventing relapse for long-time stable IgG4-RD. TRIAL REGISTRATION NUMBER: NCT04124861.
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Enfermedad Relacionada con Inmunoglobulina G4 , Inmunosupresores , Humanos , Inmunosupresores/uso terapéutico , Enfermedad Relacionada con Inmunoglobulina G4/tratamiento farmacológico , Resultado del Tratamiento , Inducción de Remisión , Glucocorticoides/uso terapéutico , RecurrenciaRESUMEN
Highly tunable electromagnetically induced transparency (EIT) with high-quality-factor (Q-factor) excited by combining with the quasi-bound states in the continuum (quasi-BIC) resonances is crucial for many applications. This paper describes all-dielectric metasurface composed of silicon cuboid etched with two rectangular holes into a unit cell and periodically arranged on a SiO2 substrate. By breaking the C2 rotational symmetry of the unit cell, a high-Q factor EIT and double quasi-BIC resonant modes are excited at 1224.3, 1251.9 and 1299.6â nm with quality factors of 7604, 10064 and 15503, respectively. We show that the EIT resonance is caused by destructive interference between magnetic dipole resonances and quasi-BIC dominated by electric quadrupole. Toroidal dipole (TD) and electric quadrupole (EQ) dominate the other two quasi-BICs. The EIT window can be successfully modulated with transmission intensity from 90% to 5% and modulation depths ranging from -17 to 24â dB at 1200-1250â nm by integrating the metasurface with an epsilon-near-zero (ENZ) material indium tin oxide (ITO) film. Our findings pave the way for the development of applications such as optical switches and modulators with many potential applications in nonlinear optics, filters, and multichannel biosensors.
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The alteration of inflammatory phenotype by macrophage polarization plays an important role in diabetic wound repair. Apigenin has been reported to be anti-inflammatory and promote tissue repair; however, whether it regulates macrophage polarization to participate in diabetic wound repair remains to be investigated. We found that apigenin promoted miR-21 expression in LPS-stimulated RAW264.7 cells, inhibited cellular M1-type factor TNF-α and IL-1ß secretion and increased M2-type factor IL-10 and TGF-ß secretion, and accelerated macrophage conversion from M1 type to M2 type, whereas this protective effect of apigenin was counteracted by a miR-21 inhibitor. Moreover, we established a macrophage-HUVECs cell in vitro co-culture system and found that apigenin accelerated the migration, proliferation, and VEGF secretion of HUVECs by promoting macrophage miR-21 expression. Further, mechanistic studies revealed that this was mediated by the TLR4/Myd88/NF-κB axis. In in vivo study, diabetic mice had significantly delayed wound healing compared to non-diabetic mice, accelerated wound healing in apigenin-treated diabetic mice, and decreased M1-type macrophages and increased M2-type macrophages in wound tissues.
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Apigenina , Diabetes Mellitus Experimental , Macrófagos , MicroARNs , Cicatrización de Heridas , Animales , MicroARNs/metabolismo , MicroARNs/genética , Apigenina/farmacología , Cicatrización de Heridas/efectos de los fármacos , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/tratamiento farmacológico , Células RAW 264.7 , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Humanos , Masculino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
OBJECTIVES: This study explores the clinical characteristics associated with the occurrence of acute anterior uveitis (AAU) in patients with axial spondyloarthritis (axSpA) within a large, multicentre database. METHODS: This observational, cross-sectional study of patients with axSpA used data from the Chinese Spondyloarthritis Registry between August 1, 2018, and March 31, 2020. The demographic and clinical features of patients with and without AAU were compared. Univariate and multivariate analyses were performed to determine the association between variables and uveitis. RESULTS: A total of 4304 patients were included in this study. The prevalence of AAU in patients with axSpA was 10.59%. Multivariate logistic regression analysis revealed a positive correlation between AAU and age at diagnosis (odds ratio [OR], 1.026; p<0.001), disease duration (OR, 2.117; p<0.001), current or past Achilles tendinitis (OR, 1.692; p<0.001), current or past dactylitis (OR, 1.687; p=0.002), current or past psoriasis (OR, 3.932; p<0.001), presence of human leukocyte antigen-B27 (HLA-B27) (OR, 2.787; p<0.001), and a good response to non-steroidal anti-inflammatory drugs (NSAIDs) (OR, 1.343; p=0.027). CONCLUSIONS: AAU was the most common extra-articular manifestation in the Chinese Spondyloarthritis Registry. In Chinese patients with axSpA, older age at diagnosis, longer disease duration, presence of HLA-B27, current or past Achilles tendinitis, current or past dactylitis, current or past psoriasis, and a good response to NSAIDs were positively associated with AAU.
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Espondiloartritis Axial , Sistema de Registros , Uveítis Anterior , Humanos , Uveítis Anterior/epidemiología , Uveítis Anterior/diagnóstico , Masculino , Femenino , Adulto , Estudios Transversales , Persona de Mediana Edad , China/epidemiología , Espondiloartritis Axial/epidemiología , Espondiloartritis Axial/tratamiento farmacológico , Espondiloartritis Axial/diagnóstico , Prevalencia , Antígeno HLA-B27/sangre , Enfermedad Aguda , Factores de Riesgo , Pueblos del Este de AsiaRESUMEN
Congenital heart disease (CHD) is one of the most significant birth defects leading to infant mortality worldwide. Circulating microRNAs (miRNAs) are emerging as novel biomarkers for the detection of cardiovascular diseases. In this study, we aimed to investigate the role of maternal serum miRNAs expression as biomarkers in the diagnosis and prediction of children with CHD. High-throughput sequencing of peripheral blood from pregnant women with abnormal and normal fetal hearts identified 1939 differentially expressed miRNAs, the first 11 of which were selected as predictive biomarkers of CHD. The expression of miRNAs in more clinical samples was then quantitatively verified by reverse transcriptase polymerase chain reaction and the correlation between abnormal miRNAs and CHD was analyzed. Two miRNAs (hsa-miR-3195 and hsa-miR-122-5p) were found to be significantly down-regulated in pregnant women with fetal CHD. By further bioinformatics analysis, we predicted that hsa-miR-3195 and hsa-miR-122-5p could induce CHD by influencing biometabolic processes. hsa-miR-3195 and hsa-miR-122-5p may serve as novel non-invasive biomarkers for prenatal detection of fetal CHD.
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Biomarcadores , Cardiopatías Congénitas , MicroARNs , Humanos , Femenino , MicroARNs/sangre , MicroARNs/genética , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/sangre , Embarazo , Biomarcadores/sangre , Adulto , Diagnóstico Prenatal/métodos , Perfilación de la Expresión Génica/métodos , Biología Computacional/métodos , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
As a typical energetic compound widely used in military activities, 2,4,6-trinitrotoluene (TNT) has attracted great attention in recent years due to its heavy pollution and wide distribution in and around the training facilities, firing ranges, and demolition sites. However, the subcellular targets and the underlying toxic mechanism of TNT remain largely unknown. In this study, we explored the toxic effects of TNT biological reduction on the mitochondrial function and homeostasis in Caenorhabditis elegans (C. elegans). With short-term exposure of L4 larvae, 10-1000 ng/mL TNT reduced mitochondrial membrane potential and adenosine triphosphate (ATP) content, which was associated with decreased expression of specific mitochondrial complex involving gas-1 and mev-1 genes. Using fluorescence-labeled transgenic nematodes, we found that fluorescence expression of sod-3 (muls84) and gst-4 (dvls19) was increased, suggesting that TNT disrupted the mitochondrial antioxidant defense system. Furthermore, 10 ng/mL TNT exposure increased the expression of the autophagy-related gene pink-1 and activated mitochondrial unfolded protein response (mt UPR), which was indicated by the increased expression of mitochondrial stress activated transcription factor atfs-1, ubiquitin-like protein ubl-5, and homeobox protein dve-1. Our findings demonstrated that TNT biological reduction caused mitochondrial dysfunction and the development of mt UPR protective stress responses, and provided a basis for determining the potential risks of energetic compounds to living organisms.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mitocondrias , Trinitrotolueno , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Trinitrotolueno/toxicidad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Transporte de Electrón/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Adenosina Trifosfato/metabolismoRESUMEN
Microplastics (MPs) are a global concern as an emerging pollutant, and the investigation on MPs in Antarctic aids in informing their global pollution assessments. Therefore, there are urgent scientific concerns regarding the environmental behavior, origins, influencing factors, and potential hazards of MPs in Antarctica. This study presents the characteristics of MPs from one ornithogenic sediment profile (coded CC) and two ornithogenic soil profiles (coded MR1 and MR2) from ice-free areas on Ross Island, Antarctica. We explored the potential sources of MPs and the main influencing factors for deposition based on their distribution with depth in the profiles. Through laser-infrared imaging spectroscopy (LDIR), a total of 30 polymer types were identified in all samples, with polyethylene terephthalate (PET) and polyvinyl chloride (PVC) as the dominant types, accounting for more than 70% of the total. The abundance of MPs in the CC sediment profile ranged from 2.83 to 394.18 items/g, while in MR1 and MR2 soil profiles, the abundance ranged from 2.25 to 1690.11 and 8.24 to 168.27 items/g, respectively. The size of MPs was mainly concentrated in the range of 20-50 µm, and possible downward movement of certain polymer types was revealed. From the perspective of temporal variation, we suggest that MPs were heavily influenced by local human activities including scientific research, fishing, and tourism, balanced by protective regulations, while no solid evidence was obtained to support strong influence from biological transport through penguins. This research enhances our understanding on the environmental behavior of MPs in the terrestrial systems of remote polar regions.
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BACKGROUND: The malignancy of melanoma is attributed to its pronounced invasiveness, extensive vascularization, and rapid tumor cell growth and metastasis. LncRNA SLNCR1 is closely associated with a variety of aggressive tumors. However, our understanding of SLNCR1 influences on malignant melanoma growth metastasis mechanism especially proangiogenic mechanism remains unclear. METHODS: The expression of SLNCR1 was evaluated in melanoma tissues, adjacent tissues, melanoma cell lines. The abilities of SLNCR1 on proliferation, migration, and angiogenesis of HUVECs were detected by CCK-8, flow cytometry, and Western blot assays. The association between SLNCR1, DNMT1, and SPRY2 was assessed by ChIP, RIP, and Western blot assays. The effect of SLNCR1 on tumor growth was determined using a xenograft model in nude mice. RESULTS: SLNCR1 was confirmed to be highly expressed in melanoma tissues and cells. CM from melanoma cells transfected with sh-SLNCR1 attenuated proliferation, migration, and angiogenesis of HUVECs. Moreover, loss of SLNCR1 hindered tumor growth and metastasis, as evidenced by reduced tumor size and weight, as well as angiogenesis. Mechanistic studies revealed that SLNCR1 silenced SPRY2 expression, likely through enhancing DNMT1-mediated DNA methylation of SPRY2 promoter. CONCLUSION: SLNCR1 is an oncogene that interacts with DNMT1 to mediate SPRY2 methylation, thereby suppressing SPRY2 expression and promoting the angiogenesis and tumor growth in melanoma. SLNCR1 may serve as a potential target for melanoma treatment.
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Proliferación Celular , ADN (Citosina-5-)-Metiltransferasa 1 , Péptidos y Proteínas de Señalización Intracelular , Melanoma , Proteínas de la Membrana , Ratones Desnudos , Neovascularización Patológica , ARN Largo no Codificante , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/patología , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neovascularización Patológica/genética , Ratones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Epigénesis Genética , Movimiento Celular/genética , Células Endoteliales de la Vena Umbilical Humana , Femenino , Regulación Neoplásica de la Expresión Génica , Masculino , AngiogénesisRESUMEN
OBJECTIVE: The objective of this study is to elucidate the causal association between asthma and alopecia areata (AA) through the application of Mendelian randomization (MR) analysis, leveraging summary data from genome-wide association studies (GWAS). Additionally, it explores potential mediating factors. MATERIALS AND METHODS: Mendelian randomization (MR) analysis was employed to investigate the causal relationship between asthma and AA using genetic instrumental variables (IVs) for asthma, 91 circulating inflammatory proteins, and AA extracted from large-scale GWAS. The primary analytical approach utilized the inverse-variance weighted (IVW) method, supplemented by weighted median and MR-Egger methods to assess robustness. Tests for heterogeneity and pleiotropy were conducted to ensure result reliability. Furthermore, the study examined the mediating role of circulating inflammatory proteins in the asthma-AA relationship. RESULTS: The findings revealed an increased risk of AA among asthma patients (odds ratio (OR) = 14.070; 95% confidence interval (CI) = 1.410-140.435; P = 0.024). Interleukin-33 (IL-33) emerged as a significant mediator in the asthma-AA relationship, explaining 13.1% of the mediation effect. Bidirectional Mendelian randomization analyses did not establish a causal effect of AA on asthma occurrence. CONCLUSION: This study, utilizing Mendelian Randomization, elucidates the causal link between asthma and AA, highlighting the mediating role of IL-33. These findings underscore the importance of considering AA risk in asthma management and offer insights for potential therapeutic strategies targeting IL-33. Future research should explore additional biomarkers and mediating mechanisms between asthma and AA to enhance treatment approaches and patient quality of life.
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Alopecia Areata , Asma , Estudio de Asociación del Genoma Completo , Interleucina-33 , Análisis de la Aleatorización Mendeliana , Humanos , Alopecia Areata/genética , Asma/genética , Asma/epidemiología , Asma/sangre , Interleucina-33/genética , Interleucina-33/sangre , Análisis de Mediación , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad/genéticaRESUMEN
BACKGROUND: The repair of facial skin and soft tissue defects remains a clinical challenge. The author introduced a novel "table tennis racquet" random skin flap for wound repair after facial skin cancer excision and discussed its survival mechanisms. METHODS: A lateral mandibular neck skin flap shaped like a table tennis racquet with no well-known blood vessels at the narrow pedicle was designed in 31 cases to repair tissue defects. Among them, there were 8 cases of skin carcinoma in the frontotemporal area and 23 cases of skin carcinoma in the cheek. The flap area was 8.0 × 7.0 cm at maximum and 3.0 × 2.5 cm at minimum, with a pedicle width of 1.0-2.0 cm and a pedicle length of 2.0-6.0 cm. RESULTS: All 31 "table tennis racquet" random skin flaps survived, although there were 3 cases with delayed healing of distal flap bruising. All of them had an ideal local shape after repair with a concealed donor area and inconspicuous scars. CONCLUSIONS: This flap has a "table tennis racquet" shape with a pedicle without well-known blood vessels and has a length-to-width ratio that exceeds that of conventional random flaps, making it unconventional. Because of its long and narrow pedicle, it not only has a large rotation and coverage area but also can be designed away from the defect area, avoiding the defect of no donor tissue being localized near the defect. Overall, this approach is an ideal option for repairing tissue defects after enlarged excision of facial skin carcinoma.
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Neoplasias Faciales , Procedimientos de Cirugía Plástica , Neoplasias Cutáneas , Colgajos Quirúrgicos , Humanos , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Faciales/cirugía , Anciano , Procedimientos de Cirugía Plástica/métodos , Colgajos Quirúrgicos/irrigación sanguínea , Resultado del Tratamiento , Trasplante de Piel/métodos , Adulto , Cicatrización de Heridas/fisiología , Anciano de 80 o más Años , Supervivencia de InjertoRESUMEN
AIM: To assess early postoperative core symptoms in oesophageal cancer patients and their relationship with resilience. BACKGROUND: Patients with oesophageal cancer face a high number of severe symptoms in the early post-operative period and require the development of an effective symptom management programme. Identifying core symptoms through network analysis helps in accurate patient care. DESIGN: A multicentre cross-sectional study. METHODS: A cross-sectional survey was conducted from August 2022 to August 2023 at three hospitals in Anhui Province, China. A total of 469 patients were recruited for this study and 418 (89.1%) patients completed this investigation. Using network analysis to find early post-operative core symptoms in oesophageal cancer patients. Multiple linear regression was used to analyse resilience factors affecting core symptoms. RESULTS: Sadness was the most core symptom in oesophageal cancer patients in the early post-operative period (rs = 1.41), followed by incision pain and difficulty breathing while resting (rs = 1.20, rs = 1.08). Resilience was significantly associated with patients' feelings of sadness, with optimism having the greatest impact on sadness (p < .01). CONCLUSION: Sadness is the most core symptom in patients in the early post-operative period and special attention should be paid to improving their level of resilience. Local symptoms and dysfunction in the early post-operative period should be treated in a synergistic manner. IMPACT: This study identifies core symptoms and their relationship to resilience in patients with oesophageal cancer in the early post-operative period. Symptoms as the main core symptom in patients in the early post-operative period, which was sadness and was significantly associated with resilience. Precise interventions can be made to target patients' core post-operative symptoms, which can help improve the effectiveness of symptom management. REPORTING METHOD: We have complied with the relevant EQUATOR research reporting checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution in the study.
RESUMEN
Lifetime-based NIR luminescent nanothermometry is ideally suited for temperature detection in living cells and in vivo, but the thermal sensitivity (Sr) modulation remains elusive. Herein, a thorough investigation is performed to unveil the shell effect on lifetime-based Sr by finely controlling the shell thickness of lanthanide-doped core-shell-shell nanoparticles. Owing to the space-dependent energy transfer and back energy transfer between Nd3+ and Yb3+ as well as the energy migration to surface quenchers, both active and inert shells can regulate the thermal-dependent nonradiative decays and NIR luminescence lifetime of Yb3+, which in turn modulates the Sr from 0.56% to 1.54% °C-1. After poly(acrylic acid) modification of the optimal architecture, the tiny nanoprobes possess robust stability to fluctuations in the microenvironment, which enables accurate temperature mapping of inflammation in the internal liver organ of living mouse. This work will provide new insights for optimizing Sr and guidance for precise temperature measurements in vivo.