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The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth.
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KRASG12D mutation-driven pancreatic ductal adenocarcinoma (PDAC) represents a major challenge in medicine due to late diagnosis and treatment resistance. Here, we report that macroautophagy (hereafter autophagy), a cellular degradation and recycling process, contributes to acquired resistance against novel KRASG12D-targeted therapy. The KRASG12D protein inhibitor MRTX1133 induces autophagy in KRASG12D-mutated PDAC cells by blocking MTOR activity, and increased autophagic flux prevents apoptosis. Mechanistically, autophagy facilitates the generation of glutamic acid, cysteine, and glycine for glutathione synthesis. Increased glutathione levels reduce reactive oxygen species production, which impedes CYCS translocation from mitochondria to the cytosol, ultimately preventing the formation of the APAF1 apoptosome. Consequently, genetic interventions (utilizing ATG5 or BECN1 knockout) or pharmacological inhibition of autophagy (with chloroquine, bafilomycin A1, or spautin-1) enhance the anticancer activity of MRTX1133 in vitro and in various animal models (subcutaneous, patient-derived xenograft, and orthotopic). Moreover, the release of histones by apoptotic cells triggers an adaptive immune response when combining an autophagy inhibitor with MRTX1133 in immunocompetent mice. These findings establish a new strategy to overcome KRASG12D-targeted therapy resistance by inhibiting autophagy-dependent glutathione synthesis.
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Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (TRM) cells in patients with AF. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell T cell receptor (TCR) sequencing identified two transcriptionally distinct CD8+ TRM cells that are modulated in AF. Spatial transcriptomic analysis of EAT and atrial tissue identified the border region between the tissues to be a region of intense inflammatory and fibrotic activity, and the addition of TRM populations to atrial cardiomyocytes demonstrated their ability to differentially alter calcium flux as well as activate inflammatory and apoptotic signaling pathways. This study identified EAT as a reservoir of TRM cells that can directly modulate vulnerability to cardiac arrhythmia.
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Tejido Adiposo , Fibrilación Atrial , Células T de Memoria , Pericardio , Fibrilación Atrial/inmunología , Fibrilación Atrial/genética , Fibrilación Atrial/patología , Fibrilación Atrial/metabolismo , Humanos , Pericardio/metabolismo , Pericardio/patología , Pericardio/inmunología , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Masculino , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Transcriptoma , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/inmunología , Femenino , Persona de Mediana Edad , Perfilación de la Expresión Génica , Anciano , Fenotipo , Señalización del Calcio , Apoptosis , Memoria Inmunológica , Transcripción Genética , Estudios de Casos y Controles , Atrios Cardíacos/patología , Atrios Cardíacos/inmunología , Atrios Cardíacos/metabolismo , Fibrosis/patología , Tejido Adiposo EpicárdicoRESUMEN
The evolution of antitumor therapies has significantly improved cancer prognosis but has concurrently resulted in cardiovascular toxicities. Understanding the biological mechanisms behind these toxicities is crucial for effective management. Immunotherapy-related cardiovascular toxicities are primarily mediated by immune cells and secreted cytokines. Chemotherapy may cause cardiovascular damage through autophagy disruption and mitochondrial dysfunction. Targeted therapies can induce toxicity through endothelin-1 (ET-1) production and cardiac signaling disruption. Radiotherapy may lead to cardiomyopathy and myocardial fibrosis by affecting endothelial cells, triggering inflammatory responses and accelerating atherosclerosis. This review provides insights into these mechanisms and strategies, aiming to enhance the clinical prevention and treatment of cardiovascular toxicities.
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OBJECTIVE: We aimed to investigate key differentially expressed immune related genes in persistent atrial fibrillation. METHODS: Gene expression profiles were downloaded from Gene Expression Omnibus (GEO) using "GEO query" package. "limma" package and "sva" package were used to conduct normalization and eliminate batch effects, respectively. We screened out differentially expressed genes (DEGs) based on "limma" package with the standard of |log fold change (FC)| ≥ 1.5 and false discovery rate (FDR) < 0.05. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed by "clusterProfler" package. We further applied LASSO to select key DEGs, and intersected key DEGs with immune related genes from ImmPort database. The ROC curve of each DEIRG was constructed to evaluate its diagnostic efficiency for AF. RESULTS: A total of 103 DEGs we were screened out, of them, 48 genes were down-regulated and 55 genes were up-regulated. Result of functional enrichment analysis show that, most of DEGs were related to immune response, inflammation, and oxidative stress. Ultimately, CYBB, RORB, S100A12, and CHGB were determined as key DEIRGs, each of which displayed a favor efficiency for diagnosing persistent AF. CONCLUSION: CYBB, RORB, S100A12, and CHGB were identified as key DEIRGs in persistent AF, and future studies are needed to further explore the underlying roles of CYBB, RORB, S100A12, and CHGB in persistent AF.
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Fibrilación Atrial , Biología Computacional , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Transcriptoma , Fibrilación Atrial/genética , Fibrilación Atrial/inmunología , Fibrilación Atrial/diagnóstico , Humanos , Redes Reguladoras de Genes , Valor Predictivo de las Pruebas , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Regulación de la Expresión GénicaRESUMEN
Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAMhigh macrophages, and exhausted CD8+ T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF-1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAMhigh macrophages co-localize with exhausted CD8+ T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF-1É inhibition reduces ALCAM expression in macrophages and exhausted CD8+ T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single-cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAMhigh macrophage-exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia-induced resistance in cancers.
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Pomelo flowers emit a strong fragrance and give aromatic odors. Volatile compounds from pomelo flowers were analyzed at three developmental stages and in the main organs by molecular sensory science. A total of 134 volatiles including 25 odorants, were analyzed by gas chromatography-mass spectrometry/pulsed flame photometric detector (GC-MS/PFPD) and multidimensional GC-MS/olfactory (MDGC-MS/O). The total volatile content varied among pomelo flowers at different developmental stages (stage-III > stage-II > stage-I) and among different organs of pomelo flowers (petal > pistil > stamen). Linalool was an important odorant with a high OAV, and floral/fruity comprised the predominant aroma profile. Four odorants, ethyl 2-methylbutanoate, linalool, ß-myrcene, and 2-butenal, were selected based on variable importance in projection (VIP) values and contributed mainly to the discrimination of pomelo flowers at three different developmental stages. Linalool, ß-myrcene, d-limonene, and ethyl hexanoate were potential markers for evaluating flavor differences in pomelo floral organs.
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The nonuniform distribution of fruit tree canopies in space poses a challenge for precision management. In recent years, with the development of Structure from Motion (SFM) technology, unmanned aerial vehicle (UAV) remote sensing has been widely used to measure canopy features in orchards to balance efficiency and accuracy. A pipeline of canopy volume measurement based on UAV remote sensing was developed, in which RGB and digital surface model (DSM) orthophotos were constructed from captured RGB images, and then the canopy was segmented using U-Net, OTSU, and RANSAC methods, and the volume was calculated. The accuracy of the segmentation and the canopy volume measurement were compared. The results show that the U-Net trained with RGB and DSM achieves the best accuracy in the segmentation task, with mean intersection of concatenation (MIoU) of 84.75% and mean pixel accuracy (MPA) of 92.58%. However, in the canopy volume estimation task, the U-Net trained with DSM only achieved the best accuracy with Root mean square error (RMSE) of 0.410 m3, relative root mean square error (rRMSE) of 6.40%, and mean absolute percentage error (MAPE) of 4.74%. The deep learning-based segmentation method achieved higher accuracy in both the segmentation task and the canopy volume measurement task. For canopy volumes up to 7.50 m3, OTSU and RANSAC achieve an RMSE of 0.521 m3 and 0.580 m3, respectively. Therefore, in the case of manually labeled datasets, the use of U-Net to segment the canopy region can achieve higher accuracy of canopy volume measurement. If it is difficult to cover the cost of data labeling, ground segmentation using partitioned OTSU can yield more accurate canopy volumes than RANSAC.
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BACKGROUND: Drug-coated balloon (DCB) angioplasty seems a safe and effective option for specific de novo coronary lesions. However, the beneficial effect of intravascular ultrasound (IVUS)-guided DCB angioplasty in de novo lesions remains uncertain. OBJECTIVES: This study aimed to assess the benefits of IVUS guidance over angiography guidance during DCB angioplasty in de novo coronary lesions. METHODS: A total of 260 patients with high bleeding risk who had a de novo coronary lesion (reference vessel diameter 2.0-4.0 mm, and lesion length ≤15 mm) were randomly assigned to either an IVUS-guided or an angioplasty-guided DCB angioplasty group. The primary endpoint was in-segment late lumen loss (LLL) at 7 months after procedure. The secondary endpoint was target vessel failure at 6 months. RESULTS: A total of 2 patients in the angiography-guided group and 7 patients in the IVUS-guided group underwent bailout stent implantation (P = 0.172). The primary endpoint of 7-month LLL was 0.03 ± 0.52 mm with angiography guidance vs -0.10 ± 0.34 mm with IVUS guidance (mean difference 0.14 mm; 95% CI: 0.02-0.26; P = 0.025). IVUS guidance was also associated with a larger 7-month minimal lumen diameter (2.06 ± 0.62 mm vs 1.75 ± 0.63 mm; P < 0.001) and a smaller diameter stenosis (28.15% ± 13.88% vs 35.83% ± 17.69%; P = 0.001) compared with angiography guidance. Five target vessel failures occurred at 6 months, with 4 (3.1%) in the angiography-guided group and 1 (0.8%) in the IVUS-guided group (P = 0.370). CONCLUSIONS: This study demonstrated that IVUS-guided DCB angioplasty is associated with a lower LLL in patients with a de novo coronary lesion compared with angiography guidance. (Intravascular Ultrasound Versus Angiography Guided Drug-Coated Balloon [ULTIMATE-III]; NCT04255043).
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Angioplastia Coronaria con Balón , Catéteres Cardíacos , Fármacos Cardiovasculares , Materiales Biocompatibles Revestidos , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Valor Predictivo de las Pruebas , Ultrasonografía Intervencional , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Resultado del Tratamiento , Factores de Tiempo , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/efectos adversos , Estudios Prospectivos , Factores de Riesgo , ChinaRESUMEN
Delayed outcome is common in phase I oncology clinical trials. It causes logistic difficulty, wastes resources, and prolongs the trial duration. This article investigates this issue and proposes the time-to-event 3 + 3 (T3 + 3) design, which utilizes the actual follow-up time for at-risk patients with pending toxicity outcomes. The T3 + 3 design allows continuous accrual without unnecessary trial suspension and is costless and implementable with pretabulated dose decision rules. Besides, the T3 + 3 design uses the isotonic regression to estimate the toxicity rates across dose levels and therefore can accommodate for any targeted toxicity rate for maximum tolerated dose (MTD). It dramatically facilitates the trial preparation and conduct without intensive computation and statistical consultation. The extension to other algorithm-based phase I dose-finding designs (e.g., i3 + 3 design) is also studied. Comprehensive computer simulation studies are conducted to investigate the performance of the T3 + 3 design under various dose-toxicity scenarios. The results confirm that the T3 + 3 design substantially shortens the trial duration compared with the conventional 3 + 3 design and yields much higher accuracy in MTD identification than the rolling six design. In summary, the T3 + 3 design addresses the delayed outcome issue while keeping the desirable features of the 3 + 3 design, such as simplicity, transparency, and costless implementation. It has great potential to accelerate early-phase drug development.
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Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation. In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency.
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Aminoácidos de Cadena Ramificada , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Microambiente Tumoral , Animales , Aminoácidos de Cadena Ramificada/metabolismo , Ratones , Humanos , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Linfocitos T/inmunología , Linfocitos T/metabolismo , Neoplasias/terapia , Neoplasias/metabolismo , Neoplasias/inmunología , Modelos Animales de EnfermedadRESUMEN
Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.
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Ferroptosis , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/etiología , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Ferroptosis/genética , Ferroptosis/efectos de los fármacos , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Citrus black spot (Phyllosticta citricarpa, CBS) is an important fungal disease that causes rind blemishes and affects quality of citrus fruits. The response of citrus to CBS in terms of volatiles was evaluated using molecular sensory science approaches. Fifty and twenty-one volatiles were identified in the orange juice and essential oil samples, respectively, via gas chromatography-mass spectrometry (GC-MS). The total volatile content in the samples increased after CBS infection, especially in the severe-infection group (SEG) juice and moderate-infection group (MOG) essential oil, which reached the highest levels. CBS enhanced floral, fruity, and off-flavor aromas and decreased the green aroma in citrus juice. Citrusy, floral, and green aromas increased in the CBS-infected essential oil. Six/five potential markers were screened in citrus juice/essential oil, respectively using the orthogonal partial least-square discriminant analysis (OPLS-DA) model. The changes in aroma profile and the difference in infection levels in citrus were attributed to these odorants.
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EVI1 expression is associated with poor prognosis in myeloid leukaemia, which can result from Chr.3q alterations that juxtapose enhancers to induce EVI1 expression via long-range chromatin interactions. More often, however, EVI1 expression occurs unrelated to 3q alterations, and it remained unclear if, in these cases, EVI1 expression is similarly caused by aberrant enhancer activation. Here, we report that, in EVI1+3q- myeloid leukaemia cells, the EVI1 promoter interacts via long-range chromatin interactions with promoters of distally located, active genes, rather than with enhancer elements. Unlike in 3q+ cells, EVI1 expression and long-range interactions appear to not depend on CTCF/cohesin, though EVI1+3q- cells utilise an EVI1 promoter-proximal site to enhance its expression that is also involved in CTCF-mediated looping in 3q+ cells. Long-range interactions in 3q- cells connect EVI1 to promoters of multiple genes, whose transcription correlates with EVI1 in EVI1+3q- cell lines, suggesting a shared mechanism of transcriptional regulation. In line with this, CRISPR interference-induced silencing of two of these sites minimally, but consistently reduced EVI1 expression. Together, we provide novel evidence of features associated with EVI1 expression in 3q- leukaemia and consolidate the view that EVI1 in 3q- leukaemia is largely promoter-driven, potentially involving long-distance promoter clustering.
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Leucemia Mieloide , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Proteínas de Unión al ADN/genética , Cromatina , Proteína del Locus del Complejo MDS1 y EV11/genética , Leucemia Mieloide/genética , Proto-OncogenesRESUMEN
Expression quantitative trait locus (eQTL) analysis is a powerful tool used to investigate genetic variations in complex diseases, including cancer. We previously developed a comprehensive database, PancanQTL, to characterize cancer eQTLs using The Cancer Genome Atlas (TCGA) dataset, and linked eQTLs with patient survival and GWAS risk variants. Here, we present an updated version, PancanQTLv2.0 (https://hanlaboratory.com/PancanQTLv2/), with advancements in fine-mapping causal variants for eQTLs, updating eQTLs overlapping with GWAS linkage disequilibrium regions and identifying eQTLs associated with drug response and immune infiltration. Through fine-mapping analysis, we identified 58 747 fine-mapped eQTLs credible sets, providing mechanic insights of gene regulation in cancer. We further integrated the latest GWAS Catalog and identified a total of 84 592 135 linkage associations between eQTLs and the existing GWAS loci, which represents a remarkable â¼50-fold increase compared to the previous version. Additionally, PancanQTLv2.0 uncovered 659516 associations between eQTLs and drug response and identified 146948 associations between eQTLs and immune cell abundance, providing potentially clinical utility of eQTLs in cancer therapy. PancanQTLv2.0 expanded the resources available for investigating gene expression regulation in human cancers, leading to advancements in cancer research and precision oncology.
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Bases de Datos Genéticas , Neoplasias , Sitios de Carácter Cuantitativo , Humanos , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Medicina de Precisión , Sitios de Carácter Cuantitativo/genéticaRESUMEN
SCOPE: Branched chain amino acids (BCAAs) are essential amino acids and important nutrient signals for energy and protein supplementation. The study uses muscle-specific branched-chain α-keto acid dehydrogenase kinase (Bckdk) conditional knockout (cKO) mice to reveal the contribution of BCAA metabolic dysfunction to muscle wasting. METHOD AND RESULTS: Muscle-specific Bckdk-cKO mice are generated through crossbreeding of Bckdkf/f mice with Myf5Cre mice. Lewis lung cancer (LLC) tumor transplantation is used to establish the cancer cachexia model. The occurrence of cancer cachexia is accelerated in the muscle-specific Bckdk-cKO mice after bearing LLC tumor. Wasting skeletal muscle is characterized by increased protein ubiquitination degradation and impaired protein synthesis. The wasting muscle gastrocnemius is mechanized as a distinct BCAA metabolic dysfunction. Based on the atrophy phenotype resulting from BCAA metabolism dysfunction, the optimized BCAA supplementation improves the survival of cancer cachexia in muscle-specific Bckdk-cKO mice bearing LLC tumors, and improves the occurrence of cancer cachexia. The mechanism of BCAA supplementation on muscle mass preservation is based on the promotion of protein synthesis and the inhibition of protein ubiquitination degradation. CONCLUSIONS: Dysfunctional BCAA metabolism contributes to the inhibition of protein synthesis and increases protein degradation in the cancer cachexia model of muscle-specific Bckdk-cKO mice bearing LLC tumors. The reprogramming of BCAA catabolism exerts therapeutic effects by stimulating protein synthesis and inhibiting protein degradation in skeletal muscle.
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Aminoácidos de Cadena Ramificada , Caquexia , Ratones Noqueados , Músculo Esquelético , Atrofia Muscular , Animales , Caquexia/metabolismo , Caquexia/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/etiología , Aminoácidos de Cadena Ramificada/metabolismo , Músculo Esquelético/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/complicaciones , Ratones , Ubiquitinación , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/metabolismo , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/genética , Masculino , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Ratones Endogámicos C57BL , Reprogramación Metabólica , Proteínas QuinasasRESUMEN
The aim was to construct and verify a nomogram-based assessment of cancer-specific survival (CSS) in patients with colorectal signet ring cell carcinoma after surgery. Patients were collected from Surveillance, Epidemiology, and End Results program between 2004 and 2015. Independent prognostic indicators were determined in the training cohort by Cox regression model. We identified 2217 eligible patients, who were further categorized into the training set (nâ =â 1693) as well as the validation set (nâ =â 524). Multivariate analysis revealed that age at diagnosis, gender, grade, tumor size, T stage, N stage, and M stage were independent predictive indicators. Then, the above 7 predictive factors were incorporated into a nomogram model to assess CSS, which showed good calibration and discrimination capacities in both sets. Both internal and external calibration plot diagrams revealed that the actual results were consistent with the predicted outcomes. The time-independent area under the curves for 3-year and 5-year CSS in the nomogram were larger than American Joint Committee on Cancer and Surveillance, Epidemiology, and End Results summary stage system. Moreover, decision curve analysis indicated the clinical utility of the nomogram. The nomogram demonstrated favorable predictive accuracy of survival in colorectal signet ring cell carcinoma patients after surgery, which should be further confirmed before clinical implementation.
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Carcinoma de Células en Anillo de Sello , Neoplasias Colorrectales , Humanos , Nomogramas , Investigación , Calibración , Carcinoma de Células en Anillo de Sello/cirugía , Neoplasias Colorrectales/cirugía , Programa de VERFRESUMEN
Osteochondral defects caused by degenerative diseases of joints, traumas and inflammation are important issues in clinical practice. Different types of autologous platelet concentrate (PCs) are used in bone and cartilage regeneration. The present study aimed to investigate the effect of lyophilized platelet-rich fibrin (L-PRF) on the repair of osteochondral defects in rabbits. L-PRF was first prepared from fresh PRF (F-PRF) through freeze-drying, and histological and microstructural observations were performed to compare the characteristics of L-PRF and F-PRF. Thereafter, these bioactive scaffolds were implanted into osteochondral defects surgically created in rabbits to assess their effects on tissue repair using micro-CT scanning, histological observations and the evaluation scoring method for cartilage repair established by the International Cartilage Repair Society (ICRS). L-PRF had a histological structure similar to F-PRF. At 16 weeks after implantation surgery, full-thickness osteochondral defects with a diameter of 5 mm and a depth of 4 mm were well-filled with newly regenerated tissues, exhibiting the simultaneous regeneration of avascular articular cartilage and well-vascularized subchondral bone, as proven through macroscopic and microscopic observations in PRF-treated groups compared with that in the untreated group. The application of L-PRF and F-PRF for osteochondral defects in rabbits contributed to massive host remodeling and reconstruction of osteochondral tissues, thus offering a prospective bioactive scaffold for the simultaneous reconstruction of articular cartilage and subchondral bone tissue.
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In this report, we present a case study of a 64-year-old female who was diagnosed with gastrointestinal stromal tumors (GISTs) and subsequently developed liver metastases despite undergoing radical resection. Next-generation sequencing (NGS) assays indicated that the tumor lacked KIT/PDGFRA/SDH/RAS-P (RAS pathways, RAS-P) mutations, thereby classifying this patient as quadruple WT GIST (qGIST). Treatment with imatinib was initiated, and after 2.5 months, recurrence of the tumor and multiple metastases around the surgical site were observed. Consequently, the patient was switched to sunitinib treatment and responded well. Although she responded well to sunitinib, the patient died of tumor dissemination within 4 months. This case study highlights the potential efficacy of imatinib and the VEGFR-TKI sunitinib in treating qGIST patients harboring a TP53 missense mutation.
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Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce degradation by the ubiquitin-proteasome system (UPS) offer new opportunities to engage targets that remain challenging to be inhibited by conventional small molecules. One fundamental element in the degradation process is the E3 ligase. However, less than 2% amongst hundreds of E3 ligases in the human genome have been engaged in current studies in the TPD field, calling for the recruiting of additional ones to further enhance the therapeutic potential of TPD. To accelerate the development of PROTACs utilizing under-explored E3 ligases, we systematically characterize E3 ligases from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, and PPI interface by analyzing 30 large-scale data sets. Our analysis uncovers several E3 ligases as promising extant PROTACs. In total, combining confidence score, ligandability, expression pattern, and PPI, we identified 76 E3 ligases as PROTAC-interacting candidates. We develop a user-friendly and flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers to rapidly identify E3 ligases with promising TPD activities against specifically desired targets, facilitating the development of these therapies in cancer and beyond.