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Due to their unique physical and chemical properties, metal-organic cage structures have great potential for applications in various fields. However, current studies have mainly focused on highly symmetric structures assembled from single metal ions and organic ligands, limiting their diversity and complexity, and there are still relatively few studies on the dynamic formation process of metal-organic cages. Herein, we constructed a series of metal-organic cages with different sizes assembled from the highly-stable coordination of 2,2':6',2''-terpyridine-based tetratopic ligands and various metals ions such as Zn, Cu, Co and Fe. Furthermore, the intermolecular exchange process between the metal-organic cages was explored through the dynamic exchange of ligands, and the formation of a series of hybrid supramolecular nanocages together with their final tendency to form a predominant structure of M24L14L28 was observed. In addition, the binding of metal-organic cages with 5,10,15,20-tetrakis(3,4,5-trimethoxyphenyl) porphyrin-Zn was also investigated. This study not only expands the complexity and diversity of metal-organic cages, but also provides a new perspective for studying the dynamic behaviour of metal-organic cages.
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RATIONALE AND OBJECTIVES: This study aimed to assess the incremental diagnostic value of non-contrast T1 mapping-derived radiomics in patients with amyloid light-chain cardiac amyloidosis (AL-CA). METHODS: We retrospectively collected 86 patients with suspected AL-CA and 28 control patients who underwent cardiac MRI at 3.0 T in our institution, and the MRI data were divided into a training set and a test set. Radiomic features were extracted based on native T1 maps using a freely available software package. We applied LASSO logistic regression method to select radiomic features with high diagnostic value of AL-CA and develop a predictive model. The diagnostic performance of the radiomics model was evaluated using receiver operating characteristic curve analysis and compared to T1 values. RESULTS: A total of 70 people were diagnosed with AL-CA, and cardiac involvement was observed in 202 myocardial slicers. The accuracy of T1 values for the diagnosis of myocardial involvement was 0.886, with a threshold value of 1375 ms. The radiomics score comprised a total of three features. The radiomics score demonstrated significantly higher sensitivity in detecting myocardial involvement compared to T1 values in both the training set (AUC 0.886 vs. 0.924, P = 0.025) and the test set (0.862 vs 0.915, P = 0.026). The combined model comprising T1 values and a radiomic feature named S(4,-4) Correlat showed higher diagnostic performance in comparison to T1 values alone both in the training and test sets, with AUC values of 0.929 and 0.909, respectively. CONCLUSION: The radiomic features derived from native T1 mapping demonstrated incremental value for the diagnosis of AL-CA, which may be an alternative to T1-derived ECV to avoid the use of contrast in patients with suspected myocardial involvement in systemic amyloidosis.
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Compared with young liver donors, aged liver donors are more susceptible to ischemia-reperfusion injury (IRI) following transplantation, which may be related to excessive inflammatory response and macrophage dysfunction, but the specific mechanism is unclear. Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, and plays an important regulatory role in inflammation response and macrophage function regulation. But its role in IRI following aged-donor liver transplantation is still unclear. This study demonstrates that MSR1 expression is decreased in macrophages from aged donor livers, inhibiting their efferocytosis and pro-resolving polarisation. Decreased MSR1 is responsible for the more severe IRI suffered by aged donor livers. Overexpression of MSR1 using F4/80-labeled AAV9 improved intrahepatic macrophage efferocytosis and promoted pro-resolving polarisation, ultimately ameliorating IRI following aged-donor liver transplantation. In vitro co-culture experiments further showed that overexpression of MSR1 promoted an increase in calcium concentration, which further activated the PI3K-AKT-GSK3ß pathway, and induced the upregulation of ß-catenin. Overall, MSR1-dependent efferocytosis promoted the pro-resolving polarisation of macrophages through the PI3K-AKT-GSK3ß pathway-induced up-regulating of ß-catenin leading to improved IRI following aged-donor liver transplantation.
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Aging-related alterations in hepatic enzyme activity, particularly of the CYP3A, significantly impact drug efficacy and safety in older adults, making it essential to understand how aging affects CYP function for optimal drug therapy. The exogenous probe substrate method, a minimally invasive approach to assess liver metabolic enzyme activity in vivo, is effective in studying these changes. Amlodipine being extensively metabolized (> 90%) in the liver, primarily via cytochrome P450 enzyme CYP3A was selected as a probe to investigate and quantify the factors affecting the aging-related changes of CYP3A in the Chinese older population. Amlodipine concentration data were collected from an ongoing noninterventional clinical study conducted at Peking University Third Hospital. A physiologically-based pharmacokinetic modeling approach, grounded in population pharmacokinetic (PPK) analysis, was employed to physiologically quantify the aging-related changes in CYP3A function. A total of 132 amlodipine concentrations from 69 patients were obtained from the clinical study. PPK analysis shows that frailty phenotype but not age is a significant influence and frail patients have 37% greater plasma amlodipine exposure than nonfrail patients. This difference in CYP3A function may be attributed to a 63.2% lower CYP3A relative abundance in the frail patients, compared with that in the nonfrail patients. In the context of dose selection for older adults, focusing on frailty rather than chronological age should be recognized as a more relevant approach, because frailty might more accurately reflect the individual's biological age. Our study suggested a need to shift the research focus from chronological age to biological age.
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Envejecimiento , Amlodipino , Pueblo Asiatico , Citocromo P-450 CYP3A , Modelos Biológicos , Humanos , Amlodipino/farmacocinética , Anciano , Citocromo P-450 CYP3A/metabolismo , Masculino , Femenino , Envejecimiento/metabolismo , Anciano de 80 o más Años , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , China , Persona de Mediana Edad , Factores de Edad , Hígado/metabolismo , Hígado/enzimología , Anciano Frágil , Bloqueadores de los Canales de Calcio/farmacocinética , Pueblos del Este de AsiaRESUMEN
Background: Pancreatic adenocarcinoma (PAAD) is a formidable challenge in oncology research, with a complex pathogenesis that requires to be explored. Major Vault Protein (MVP) is the principal structural component of the vault complex, and its expression level is remarkably upregulated in various cancers. Extensive investigations have been conducted to explore the role of MVP in specific cancer contexts, yet the potential molecular mechanisms and biological functions of MVP in PAAD still remain considerably elusive. This study aims to explore the role of MVP as a novel immune-related biomarker in the pathogenesis and clinical treatment of PAAD. Methods: Gene expression data and clinical information were collected from TCGA, GTEx and GEO databases. Survival, prognostic and functional enrichment analysis were employed with R software. Immunological correlation analysis was performed using TIMER2.0, TIDE scores, TISIDB and TISCH. Epigenetic analysis was implemented by MethSurv, CPTAC, UALCAN, and cBioPortal. Drug analysis was conducted using Enrichr and CellMiner. Moreover, cellular experiments, like RNA interference, qRT-PCR, Western blot, cell cycle analysis, cell apoptosis analysis, colony formation assay, transwell assay, and wound healing assay, were performed for verifying the functional properties of MVP in the PAAD progression. Results: We demonstrated an abnormally upregulated expression of MVP in PAAD tissues, which notably correlated with an adverse prognosis in PAAD patients. Functional analysis suggested the conceivable involvement of MVP in immune modulation, and immunotherapy. Additionally, we identified genetic alterations, reduced promoter methylation, and heightened phosphorylation in MVP. We also clarified Suloctidil and Tetradioxin as the most notable potential drugs targeting MVP in PAAD. Moreover, our experimental observations consistently highlighted the significant impact of MVP deficiency on impeding PAAD cell proliferation, inhibiting cell migration, and accelerating cell apoptosis. Interestingly, a potential link between MVP and ERK or AKT pathways was displayed, which opens new avenues for further exploration of the molecular mechanisms of MVP-targeted therapies in PAAD. Conclusions: This study systematically describes MVP as an immune-related biomarker with remarkable potential for predicting the prognosis, tumor progression and immunotherapeutic efficacy in PAAD.
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Adenocarcinoma , Biomarcadores de Tumor , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas , Partículas Ribonucleoproteicas en Bóveda , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Partículas Ribonucleoproteicas en Bóveda/genética , Partículas Ribonucleoproteicas en Bóveda/metabolismo , Adenocarcinoma/inmunología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Línea Celular Tumoral , Pronóstico , ApoptosisRESUMEN
BACKGROUND: Obstructive Sleep Apnea (OSA) is a widespread sleep disturbance linked to metabolic and cardiovascular conditions. The Non-High-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol Ratios (NHHR) has been proposed as being a potential biomarker to gauge cardiovascular risk. However, its relationship with OSA remains unclear. METHODS: This survey investigated the link NHHR to OSA in American citizens aged 20 and older using information collected via the National Health and Nutrition Examination Survey (NHANES) during the years 2017 to 2020. Logistic regression models with multivariable adjustments were employed to assess this relationship. Nonlinear associations were explored using smooth curve fitting, with a two-part linear regression model identifying a threshold effect. Subgroup analyses were conducted to evaluate population-specific differences. RESULTS: The survey encompassed 6763 participants, with an average age of 50.75 ± 17.32. The average NHHR stood at 2.74, accompanied by a standard deviation of 1.34, while the average frequency of OSA was 49.93%. Upon adjusting for covariates, each unit increase in NHHR may be associated with a 9% rise in OSA incidence. (95% confidence intervals 1.04-1.14; P < 0.0001). Notably, a U-shaped curve depicted the NHHR-OSA relationship, with an inflection point at 4.12. Subgroup analyses revealed consistent associations, with educational attainment and diabetes status modifying the NHHR-OSA relationship. CONCLUSION: The study highlights NHHR as a potential tool for OSA prediction, presenting avenues for advanced risk evaluation, tailored interventions, personalized treatment approaches, and preventive healthcare.
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HDL-Colesterol , Encuestas Nutricionales , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/epidemiología , Persona de Mediana Edad , Masculino , Femenino , Estudios Transversales , Adulto , HDL-Colesterol/sangre , Anciano , Factores de Riesgo , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiologíaRESUMEN
Background: This study aimed to evaluate the effectiveness of using animation as education material for family empowerment program on perioperative care for caregivers whose children were to undergo neurosurgery. Methods: A total of 204 caregivers were randomly assigned to either the face-to-face oral nursing educated group (Oral Group) or the animation-assisted nursing educated group (Animated Group). The nursing education primarily focused on instructing caregivers about the manual vibration method. The primary outcome of interest in this study was participants' knowledge level, collected by a 10-item questionnaire. Secondary outcomes included child patients' clinical data, including hospitalization days, treatments, and signs of pneumonia. Results: Participants in the Animated Group exhibited significantly higher accuracy in perioperative care knowledge assessment, and patients in this group had a lower chance of requiring atomization therapy compared to the Oral Group. Conclusions: The animation-assisted nursing education program effectively enhances pediatric caregivers' knowledge, reduces respiratory complications after surgery, and offers valuable insights for future studies on the use of such programs to instruct caregivers.
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Circular RNAs (circRNAs) have been reported to be associated with the malignant phenotypes of cancer. However, the role and underlying mechanism of hsa_Circ_0008035 in colorectal cancer (CRC) remains unclear. In this study, we elucidated the pivotal role of hsa_circ_0008035 in gastric cancer progression and immune evasion. Elevated hsa_circ_0008035 levels in gastric cancer patient serum correlated positively with disease advancement, including tumor stages and lymph node metastasis. Functional analyses revealed a negative association between hsa_circ_0008035 and CD8+ T cell number and function. Mechanistically, hsa_circ_0008035 encoded the novel protein EXT1-219aa, suppressing EXT1 phosphorylation and expression. Additionally, hsa_circ_0008035 regulated pyruvate metabolism by influencing the nucleus localization of PKM2. The identified EXT1/PKM2 axis further underscored the intricate regulatory mechanisms orchestrated by hsa_circ_0008035 in gastric cancer, offering potential diagnostic and therapeutic implications in the ongoing pursuit of targeted therapies for gastric cancer patients.
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In this study, we conducted an in-depth exploration of Alzheimer's Disease (AD) by integrating state-of-the-art methodologies, including single-cell RNA sequencing (scRNA-seq), weighted gene co-expression network analysis (WGCNA), and a convolutional neural network (CNN) model. Focusing on the pivotal role of microglia in AD pathology, our analysis revealed 11 distinct microglial subclusters, with 4 exhibiting obviously alterations in AD and HC groups. The investigation of cell-cell communication networks unveiled intricate interactions between AD-related microglia and various cell types within the central nervous system (CNS). Integration of WGCNA and scRNA-seq facilitated the identification of critical genes associated with AD-related microglia, providing insights into their involvement in processes such as peptide chain elongation, synapse-related functions, and cell adhesion. The identification of 9 hub genes, including USP3, through the least absolute shrinkage and selection operator (LASSO) and COX regression analyses, presents potential therapeutic targets. Furthermore, the development of a CNN-based model showcases the application of deep learning in enhancing diagnostic accuracy for AD. Overall, our findings significantly contribute to unraveling the molecular intricacies of microglial responses in AD, offering promising avenues for targeted therapeutic interventions and improved diagnostic precision.
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Enfermedad de Alzheimer , Microglía , Redes Neurales de la Computación , Análisis de la Célula Individual , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Análisis de la Célula Individual/métodos , Microglía/metabolismo , Microglía/patología , Humanos , Redes Reguladoras de Genes , Perfilación de la Expresión Génica , Aprendizaje ProfundoRESUMEN
Stimuli-responsive antioxidant Pickering emulsions play crucial role in many industrial areas. This study demonstrated for the first time oil-in-water Pickering emulsions with outstanding antioxidation and responsive demulsification stabilized by functionalized cellulose nanocrystals (CNCs). Dialdehyde cellulose nanocrystals (DACs) were first prepared through the oxidation of CNCs with periodate, followed by the grafting of p-aminophenols (PAPs) onto their surfaces through Schiff base reaction, affording PAP grafted DACs (DAC-g-PAP) via dynamic covalent linkage. The degree of the oxidation (DO) of DACs had a significant effect on the yield of the targeting DAC-g-PAP nanoparticles. High DO (≥40 %) potentially led to the degradation of DACs during the grafting of PAP. The introduced PAP endowed DACs with excellent radical scavenging capability, thereby providing antioxidant properties while improving the hydrophobicity. DAC-g-PAP nanoparticles were then applied as Pickering emulsifiers to prepare oil-in-water Pickering emulsions. The resultant Pickering emulsions indicated exceptional antioxidant and pH-responsiveness together with good freezing-thaw stability. The structures of DAC-g-PAP nanoparticles were thoroughly characterized in this study.
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Antioxidantes , Celulosa , Emulsiones , Nanopartículas , Emulsiones/química , Nanopartículas/química , Celulosa/química , Celulosa/análogos & derivados , Antioxidantes/química , Concentración de Iones de Hidrógeno , Oxidación-Reducción , Interacciones Hidrofóbicas e Hidrofílicas , Agua/químicaRESUMEN
Vardenafil hydrochloride tablet is an inhibitor of phosphodiesterase type 5, primarily for the treatment of erectile dysfunction. This postprandial study evaluated the pharmacokinetics and bioequivalence of the test and reference formulations of vardenafil hydrochloride tablets in healthy Chinese volunteers. An open, randomized, single-center, single-dose, 2-period, 2-sequence bioequivalence test was conducted on 66 healthy subjects under fed conditions. Subjects were randomly assigned to a 20-mg test or reference formulation with a 7-day washout period. Venous blood samples (4 mL) were collected from each subject 25 times spanning predose (0 hour) to 24 hours after dosing. The plasma concentration of vardenafil was determined by high-performance liquid chromatography-tandem mass spectrometry. Sixty-two volunteers completed the study. Under fed conditions, the maximum plasma concentration was 29.1 ng/mL, the area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration was 85.3 ngâ¢h/mL, and AUC from time 0 to infinity was 87.1 ngâ¢h/mL. The 90% confidence intervals of the geometric mean ratio of AUC time 0 to the time of the last measurable concentration and AUC from time 0 to infinity were within the bioequivalence acceptance range of 0.80-1.25. The test formulation was a bioequivalent alternative to the reference formulation when taken under fed conditions in healthy Chinese subjects.
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Área Bajo la Curva , Pueblo Asiatico , Voluntarios Sanos , Inhibidores de Fosfodiesterasa 5 , Equivalencia Terapéutica , Diclorhidrato de Vardenafil , Humanos , Diclorhidrato de Vardenafil/farmacocinética , Diclorhidrato de Vardenafil/administración & dosificación , Masculino , Adulto , Adulto Joven , Inhibidores de Fosfodiesterasa 5/farmacocinética , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Inhibidores de Fosfodiesterasa 5/sangre , Espectrometría de Masas en Tándem , Comprimidos , Cromatografía Líquida de Alta Presión , Estudios Cruzados , China , Periodo Posprandial , Pueblos del Este de AsiaRESUMEN
Temporal compressive coherent diffraction imaging is a lensless imaging technique with the capability to capture fast-moving small objects. However, the accuracy of imaging reconstruction is often hindered by the loss of frequency domain information, a critical factor limiting the quality of the reconstructed images. To improve the quality of these reconstructed images, a method dual-domain mean-reverting diffusion model-enhanced temporal compressive coherent diffraction imaging (DMDTC) has been introduced. DMDTC leverages the mean-reverting diffusion model to acquire prior information in both frequency and spatial domain through sample learning. The frequency domain mean-reverting diffusion model is employed to recover missing information, while hybrid input-output algorithm is carried out to reconstruct the spatial domain image. The spatial domain mean-reverting diffusion model is utilized for denoising and image restoration. DMDTC has demonstrated a significant enhancement in the quality of the reconstructed images. The results indicate that the structural similarity and peak signal-to-noise ratio of images reconstructed by DMDTC surpass those obtained through conventional methods. DMDTC enables high temporal frame rates and high spatial resolution in coherent diffraction imaging.
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Objective: DNA methylation is an essential epigenetic marker governed by DNA methyltransferases (DNMTs), which can influence cancer onset and progression. However, few studies have provided an integrated analysis of the relevance of DNMT family genes to cell stemness, the tumor microenvironment (TME), and immunotherapy biomarkers across diverse cancers. Methods: This study investigated the impact of five DNMTs on transcriptional profiles, prognosis, and their association with Ki67 expression, epithelial-mesenchymal transition signatures, stemness scores, the TME, and immunological markers across 31 cancer types from recognized public databases. Results: The results indicated that DNMT1/DNMT3B/DNMT3A expression increased, whereas TRDMT1/DNMT3L expression decreased in most cancer types. DNMT family genes were identified as prognostic risk factors for numerous cancers, as well as being prominently associated with immune, stromal, and ESTIMATE scores, as well as with immune-infiltrating cell levels. Expression of the well-known immune checkpoints, PDCD1 and CILA4, was noticeably related to DNMT1/DNMT3A/DNMT3B expression. Finally, we validated the role of DNMT1 in MCF-7 and HepG2-C3A cell lines through its knockdown, whereafter a decrease in cell proliferation and migration ability in vitro was observed. Conclusion: Our study comprehensively expounded that DNMT family genes not only behave as promising prognostic factors but also have the potential to serve as therapeutic targets in cancer immunotherapy for various types of cancer.
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ADN (Citosina-5-)-Metiltransferasas , Metilación de ADN , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Pronóstico , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Epigénesis Genética , Perfilación de la Expresión Génica , Proliferación Celular , Biología Computacional/métodos , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismoRESUMEN
TGA-binding (TGA) transcription factors, characterized by the basic region/leucine zipper motif (bZIP), have been recognized as pivotal regulators in plant growth, development, and stress responses through their binding to the as-1 element. In this study, the TGA gene families in melon, watermelon, cucumber, pumpkin, and zucchini were comprehensively characterized, encompassing analyses of gene/protein structures, phylogenetic relationships, gene duplication events, and cis-acting elements in gene promoters. Upon transient expression in Nicotiana benthamiana, the melon CmTGAs, with typical bZIP and DOG1 domains, were observed to localize within the nucleus. Biochemical investigation revealed specific interactions between CmTGA2/3/5/8/9 and CmNPR3 or CmNPR4. The CmTGA genes exhibited differential expression patterns in melon plants in response to different hormones like salicylic acid, methyl jasmonate, and ethylene, as well as a fungal pathogen, Stagonosporopsis cucurbitacearum that causes gummy stem blight in melon. The overexpression of CmTGA3, CmTGA8, and CmTGA9 in Arabidopsis plants resulted in the upregulation of AtPR1 and AtPR5 expression, thereby imparting enhanced resistance to Pseudomonas syringae pv. Tomato DC3000. In contrast, the overexpression of CmTGA7 or CmTGA9 resulted in a compromised resistance to Botrytis cinerea, coinciding with a concomitant reduction in the expression levels of AtPDF1.2 and AtMYC2 following infection with B. cinerea. These findings shed light on the important roles of specific CmTGA genes in plant immunity, suggesting that genetic manipulation of these genes could be a promising avenue for enhancing plant immune responses.
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Arabidopsis , Cucurbitaceae , Resistencia a la Enfermedad , Regulación de la Expresión Génica de las Plantas , Enfermedades de las Plantas , Proteínas de Plantas , Arabidopsis/genética , Arabidopsis/microbiología , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Cucurbitaceae/genética , Cucurbitaceae/microbiología , Plantas Modificadas Genéticamente , Familia de Multigenes , Filogenia , Expresión Génica Ectópica , Genoma de Planta , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismoRESUMEN
Programmed Death Receptor 1 (PD-1) inhibitors, when combined with chemotherapy, have exhibited notable effectiveness in enhancing the survival outcomes of patients afflicted with advanced gastric cancer. However, it is important to acknowledge that not all patients derive substantial benefits from this therapeutic approach, highlighting the crucial necessity of identifying efficacious biomarkers to inform immunotherapy interventions. In this study, we sought to investigate the predictive utility of circulating tumor DNA (ctDNA) as a biomarker in a cohort of 30 patients diagnosed with advanced gastric cancer, all of whom underwent first-line treatment involving PD-1 inhibitor administration alongside chemotherapy. We procured peripheral blood samples both at baseline and following the completion of two treatment cycles. Additionally, baseline tissue specimens were collected for the purpose of genomic alteration assessment, employing both 47-gene and 737-gene next-generation sequencing panels for plasma and tumor tissue, respectively. We delineated a ctDNA response as the eradication of maximum variant allele frequencies relative to baseline levels. Notably, the objective response rate among individuals exhibiting a ctDNA response proved significantly superior in comparison to non-responders (P = 0.0073). Furthermore, patients who manifested a ctDNA response experienced markedly prolonged progression-free survival (PFS) and overall survival (OS) when juxtaposed with those devoid of a ctDNA response (median PFS: 15.6 vs. 6.0 months, P = 0.003; median OS: not reached [NR] vs. 9.0 months, P = 0.011). In summation, patients with advanced gastric cancer receiving first-line treatment with PD-1 inhibitors and chemotherapy, dynamic changes in ctDNA can serve as a potential biomarker for predicting treatment efficacy and long-term outcomes.
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Biomarcadores de Tumor , ADN Tumoral Circulante , Inhibidores de Puntos de Control Inmunológico , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/sangre , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.
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Alcaloides de Amaryllidaceae , Tetracloruro de Carbono , Células Estrelladas Hepáticas , Janus Quinasa 2 , Cirrosis Hepática , Fenantridinas , Proteínas Proto-Oncogénicas c-akt , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Alcaloides de Amaryllidaceae/farmacología , Tetracloruro de Carbono/toxicidad , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Masculino , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Fenantridinas/farmacología , Fenantridinas/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Endogámicos C57BL , Línea CelularRESUMEN
Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.
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Adenosina Trifosfato , Mitocondrias , Poro de Transición de la Permeabilidad Mitocondrial , Animales , Adenosina Trifosfato/metabolismo , Ratones , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Mitocondrias/metabolismo , Humanos , Forma Mitocondrial de la Creatina-Quinasa/metabolismo , Forma Mitocondrial de la Creatina-Quinasa/genética , Transducción de Señal/fisiología , Modelos Animales de EnfermedadRESUMEN
In recent years, cyclic peptides have emerged as a promising therapeutic modality due to their diverse biological activities. Understanding the structures of these cyclic peptides and their complexes is crucial for unlocking invaluable insights about protein target-cyclic peptide interaction, which can facilitate the development of novel-related drugs. However, conducting experimental observations is time-consuming and expensive. Computer-aided drug design methods are not practical enough in real-world applications. To tackles this challenge, we introduce HighFold, an AlphaFold-derived model in this study. By integrating specific details about the head-to-tail circle and disulfide bridge structures, the HighFold model can accurately predict the structures of cyclic peptides and their complexes. Our model demonstrates superior predictive performance compared to other existing approaches, representing a significant advancement in structure-activity research. The HighFold model is openly accessible at https://github.com/hongliangduan/HighFold.
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Disulfuros , Péptidos Cíclicos , Péptidos Cíclicos/química , Disulfuros/química , Programas Informáticos , Modelos Moleculares , Conformación Proteica , Algoritmos , Biología Computacional/métodosRESUMEN
In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1-4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI-MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure-activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into ß cells, thereby promoting the regeneration of pancreatic ß cells.
RESUMEN
Human leukocyte antigen (HLA) molecules play critically significant role within the realm of immunotherapy due to their capacities to recognize and bind exogenous antigens such as peptides, subsequently delivering them to immune cells. Predicting the binding between peptides and HLA molecules (pHLA) can expedite the screening of immunogenic peptides and facilitate vaccine design. However, traditional experimental methods are time-consuming and inefficient. In this study, an efficient method based on deep learning was developed for predicting peptide-HLA binding, which treated peptide sequences as linguistic entities. It combined the architectures of textCNN and BiLSTM to create a deep neural network model called APEX-pHLA. This model operated without limitations related to HLA class I allele variants and peptide segment lengths, enabling efficient encoding of sequence features for both HLA and peptide segments. On the independent test set, the model achieved Accuracy, ROC_AUC, F1, and MCC is 0.9449, 0.9850, 0.9453, and 0.8899, respectively. Similarly, on an external test set, the results were 0.9803, 0.9574, 0.8835, and 0.7863, respectively. These findings outperformed fifteen methods previously reported in the literature. The accurate prediction capability of the APEX-pHLA model in peptide-HLA binding might provide valuable insights for future HLA vaccine design.