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The central nervous system (CNS) is less prone to infection owing to protection from the brain-blood barrier. However, craniotomy destroys this protection and increases the risk of infection in the brain of patients who have undergone craniotomy. CNS infection after craniotomy significantly increases the patient's mortality rate and disability. Controlling the occurrence of intracranial infection is very important for post-craniotomy patients. CNS infection after craniotomy is caused by several factors such as preoperative, intraoperative, and post-operative factors. Craniotomy may lead to postsurgical intracranial infection, which is mainly associated with surgery duration, infratentorial (posterior fossa) surgery, cerebrospinal fluid leakage, drainage tube placement, unregulated use of antibiotics, glucocorticoid use, age, diabetes, and other systemic infections. Understanding the risk factors of CNS infection after craniotomy can benefit reducing the incidence of intracranial infectious diseases. This will also provide the necessary guidance and evidence in clinical practice for planning to control intracranial infection in patients with craniotomy.
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BACKGROUND: Ocular neovascular diseases, which contribute significantly to vision loss, lack effective preventive treatments. Recent studies have highlighted the significant involvement of immune cells in neovascular retinopathy. Myeloid-derived suppressor cells (MDSCs) promote the development of neovascularization, but it is unknown whether they participate in pathological neovascularization and whether they are expected to be a therapeutic target. METHOD: We investigated the role of MDSCs in promoting pathological angiogenesis using an oxygen-induced retinopathy (OIR) model, employing flow cytometry, immunofluorescence, and smart-seq analysis. Then, we evaluated the proportion of MDSCs in patient blood samples using flow cytometry. Additionally, we assessed the effect of MDSC depletion using an anti-Gr-1 monoclonal antibody on retinal vasculopathy and alterations in retinal microglia. RESULTS: In the OIR model, an elevated ratio of MDSCs was observed in both blood and retinal tissue during phase II (Neovascularization). The depletion of MDSCs resulted in reduced retinal neovascularization and vaso-obliteration, along with a decrease in microglia within the neovascularization area. Furthermore, analysis of gene transcripts associated with MDSCs indicated activation of vascular endothelial growth factor (VEGF) regulation and inflammation. Importantly, infants with ROP exhibited a higher proportion of MDSCs in their blood samples. CONCLUSION: Our results suggested that excessive MDSCs represent an unrecognized feature of ocular neovascular diseases and be responsible for the retinal vascular inflammation and angiogenesis, providing opportunities for new therapeutic approaches to ocular neovascular disease.
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Células Supressoras Mieloides , Neovascularização Retiniana , Humanos , Células Supressoras Mieloides/metabolismo , Neovascularização Retiniana/patologia , Neovascularização Retiniana/metabolismo , Animais , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos , Retinopatia da Prematuridade/patologia , Retinopatia da Prematuridade/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Microglia/patologia , Microglia/metabolismo , Lactente , Oxigênio/sangueRESUMO
Elevated levels of various cellular inflammatory markers have been observed in patients with endometriosis (EMs). However, a causal relationship between these markers and EMS has not been firmly established. This study aimed to assess the causality between cellular inflammatory markers and the onset of EMS using a bidirectional Mendelian randomization approach. Genetic associations for EMs were derived from the largest and most recent genome-wide association study (GWAS) involving 1937 EMS cases and 245,603 controls of European ancestry. Single nucleotide polymorphisms associated with 41 cellular cytokines and other systemic inflammatory regulators were identified from 8293 Finnish participants. Estimates were obtained using inverse-variance weighted, with sensitivity analyses conducted using MR-Egger, weighted median, and MR-PRESSO. Among the 41 systemic inflammatory regulators included in the analysis, none were associated with the risk of EMs. Elevated levels of IL-6 were associated with an increased risk of EMs (ORâ =â 1.351, 95%CIâ =â 1.015-1.797). Conversely, genetically predicted elevated levels of platelet-derived growth factor (PDGF-BB) were associated with a reduced risk of EMs (ORâ =â 0.856, 95%CIâ =â 0.742-0.987). Genetically predicted elevations in IL-6 may contribute to an increased risk of EMs, while elevated PDGF-BB levels appear protective, suggesting potential therapeutic targets for EMs. Other systemic inflammatory regulators seem unrelated to EMs risk, potentially representing downstream effects or consequences of shared factors between inflammation and EMs.
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Endometriose , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Endometriose/genética , Endometriose/sangue , Feminino , Interleucina-6/genética , Interleucina-6/sangue , Inflamação/genética , Inflamação/sangue , Citocinas/sangue , Citocinas/genética , Finlândia/epidemiologia , Predisposição Genética para DoençaRESUMO
Epithelial ovarian cancer (EOC) is a deadly disease with limited diagnostic biomarkers and therapeutic targets. Here we conduct a comprehensive proteomic profiling of ovarian tissue and plasma samples from 813 patients with different histotypes and therapeutic regimens, covering the expression of 10,715 proteins. We identify eight proteins associated with tumor malignancy in the tissue specimens, which are further validated as potential circulating biomarkers in plasma. Targeted proteomics assays are developed for 12 tissue proteins and 7 blood proteins, and machine learning models are constructed to predict one-year recurrence, which are validated in an independent cohort. These findings contribute to the understanding of EOC pathogenesis and provide potential biomarkers for early detection and monitoring of the disease. Additionally, by integrating mutation analysis with proteomic data, we identify multiple proteins related to DNA damage in recurrent resistant tumors, shedding light on the molecular mechanisms underlying treatment resistance. This study provides a multi-histotype proteomic landscape of EOC, advancing our knowledge for improved diagnosis and treatment strategies.
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Carcinoma Epitelial do Ovário , Proteínas , Proteoma , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Biomarcadores Tumorais/sangue , Aprendizado de Máquina , Mutação , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Prognóstico , Reparo do DNA/genética , Proteínas/genética , Proteínas/metabolismo , ChinaRESUMO
BACKGROUND: Solid pediatric tumors refer to cancers that affect children and adoles-cents, and they present unique challenges due to their distinct biological characteristics and their vulnerability to young patients. This study aims to shed light on addressing anemia and the causes of anemia in patients with solid pediatric tumors. MATERIALS AND METHODS: This retrospective cohort comprised 200 healthy children as controls and 235 patients with solid tumors. The study was conducted at first Affiliated Hospital of Zhengzhou University between January 2020 and June 2023. We evaluated different parameters of blood components in controls and patients with solid tumors such as medulloblastoma, neuroblastoma, rhabdomyosarcoma, germ cell tumors, hepatoblastoma and nephroblastoma before and patients with only these tumors 3 weeks after the first cycle of chemotherapy. Further, we evaluated the relationship between serum ferritin and the weight of patients and assessed the relationship be-tween anemia and metastasis to the bone marrow in patients with neuroblastoma and hepatoblas-toma. RESULTS: We observed various combinations of derangements in blood parameters such as hemo-globin, red blood cells, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscu-lar hemoglobin concentration, hematocrit, red cell distribution width, white blood cells, and plate-let in medulloblastoma, neuroblastoma, rhabdomyosarcoma, germ cell tumors, hepatoblastoma and nephroblastoma before and 3 weeks after first cycle of chemotherapy. We found a significant correlation between serum ferritin levels and weight in neuroblastoma patients who are ≤ 2 years (p = 0.022). Involvement of tumor cells in bone marrow correlates with decreased Hb levels in both neuroblastoma (CI = 93.21-106.68, p = 0.001) and hepatoblastoma (CI = 113.36-121.00, p = 0.001). CONCLUSION: Anemia may manifest as an early symptom in neuroblastoma, hepatoblastoma, and nephroblastoma. Also, anemia may be worse in patients with neuroblastoma and hepatoblastoma after chemotherapy and might warrant anemia therapy.
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INDRODUCTION: The contour of the temple area can significantly influence the overall facial shape and proportions. To date, various methods and techniques have been used to augment the deficient temporal fossa; however, each of these approaches has certain inherent limitations. The present study aimed to transfer the temporoparietal fascia flap (TPFF) to the frontotemporal regions for aesthetic temporal augmentation. METHODS: This was a retrospective study of 13 cases with temporal depression who underwent a TPFF procedure for aesthetic temporal augmentation. These cases were operated for three years, from January 1, 2020, to December 1, 2023, at Nanjing Second Hospital, Nanjing, China. RESULTS: The data of bilateral temple width showed a measurement of 12.20 ± 0.53 cm (preoperative) and 14.36 ± 0.41 cm (postoperative), with a statistically significant difference (p < 0.001). There were no postoperative complications, including hematomas, infection, or facial nerve injuries. All patients were followed for 6 to 48 months (mean: 18 months) and exhibited cosmetic improvement. Overall, 10 patients were satisfied with the aesthetic results, while 3 were unsatisfied due to undercorrected depression. During the follow-up period, the temple volume was maintained. The frontal temple exhibited a smooth contour, and scalp baldness at the incision site was inconspicuous. CONCLUSIONS: Compared with other methods, the pedicled TPFF flap transfer is a safe and effective technique for correcting depressions in the frontotemporal regions. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors. www.springer.com/00266 .
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Emamectin benzoate (EMB), commonly used as an insecticide in fishery production, inevitably leaves residual chemicals in aquatic environments. High-level EMB exposure can cause severe damage to multiple systems of marine animals, potentially through mechanisms involving severe mitochondrial damage and oxidative stress. However, it is not clear yet how EMB exposure at a certain level can cause damage to fish kidney tissue. In this study, we exposed carps to an aquatic environment containing 2.4 µg/L of EMB and cultured carp kidney cells in vitro, established a cell model exposed to EMB. Our findings revealed that EMB exposure resulted in severe kidney tissue damage in carp and compromised the viability of grass carp kidney cells (CIK cells). By RNA-seq analysis, EMB exposure led to significant differences in mitochondrial homeostasis, response to ROS, ferroptosis, and autophagy signals in carp kidney tissue. Mechanistically, EMB exposure induced mitochondrial oxidative stress by promoting the generation of mitochondrial superoxide and reducing the activity of antioxidant enzymes. Additionally, EMB exposure triggered loss of mitochondrial membrane potential, an imbalance in mitochondrial fusion/division homeostasis, and dysfunction in oxidative phosphorylation, ultimately impairing ATP synthesis. Notably, EMB exposure also accelerated excessive autophagy and ferroptosis of cells by contributing to the formation of lipid peroxides and autophagosomes, and the deposition of Fe2+. However, N-acetyl-L-cysteine (NAC) treatment alleviated the damage and death of CIK cells by inhibiting oxidative stress. Overall, our study demonstrated that EMB exposure induced mitochondrial oxidative stress, impaired mitochondrial homeostasis, and function, promoted autophagy and ferroptosis of kidney cells, and ultimately led to kidney tissue damage in carp. Our research enhanced the toxicological understanding on EMB exposure and provides a model reference for comparative medicine.
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Autofagia , Carpas , Ferroptose , Ivermectina , Rim , Mitocôndrias , Estresse Oxidativo , Animais , Carpas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ivermectina/análogos & derivados , Ivermectina/toxicidade , Ferroptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Autofagia/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Inseticidas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
In ovarian cancer (OC), identifying key molecular players in disease escalation and chemoresistance remains critical. Our investigation elucidates the role of the DNA polymerase mu (POLM), especially G312R mutation, in propelling oncogenesis through dual pathways. POLMG312R markedly augments the ribonucleotide insertion capability of POLM, precipitating genomic instability. In addition, our research reveals that POLMG312R perturbs collagen alpha-1 (XI) chain (COL11A1) expression-a gene that plays a key role in oncogenesis-and modulates the NF-κB signaling pathway, alters the secretion of downstream inflammatory cytokines, and promotes tumor-macrophage interactions. We illustrate a bidirectional regulatory interaction between POLM, particularly its G312R variant, and COL11A1. This interaction regulates NF-κB signaling, culminating in heightened malignancy and resistance to chemotherapy in OC cells. These insights position the POLM as a potential molecular target for OC therapy, shedding light on the intricate pathways underpinning POLM variant disease progression.NEW & NOTEWORTHY Our research reveals that POLM plays an important role in ovarian cancer development, especially the mutation G312R. We uncover the POLMG312R mutation as a driver of genomic instability in ovarian cancer via aberrant ribonucleotide incorporation. We reveal that POLMG312R upregulates COL11A1 and activates NF-κB signaling, contributing to tumor progression and chemoresistance. This study identifies the POLM-COL11A1-NF-κB axis as a novel oncogenic pathway.
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Colágeno Tipo XI , Instabilidade Genômica , NF-kappa B , Neoplasias Ovarianas , Transdução de Sinais , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Instabilidade Genômica/genética , NF-kappa B/metabolismo , NF-kappa B/genética , Colágeno Tipo XI/genética , Colágeno Tipo XI/metabolismo , Linhagem Celular Tumoral , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Mutação , AnimaisRESUMO
Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.
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Carcinoma Hepatocelular , Éxons , Neoplasias Hepáticas , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases , Spliceossomos , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Acetilação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Spliceossomos/metabolismo , Spliceossomos/efeitos dos fármacos , Linhagem Celular Tumoral , Ftalazinas/farmacologia , Éxons/genética , Piperazinas/farmacologia , Animais , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Camundongos , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the COVID-19 disease, which represents a new life-threatening disaster. Regarding viral infection, many therapeutics have been investigated to alleviate the epidemiology such as vaccines and receptor decoys. However, the continuous mutating coronavirus, especially the variants of Delta and Omicron, are tended to invalidate the therapeutic biological product. Thus, it is necessary to develop molecular entities as broad-spectrum antiviral drugs. Coronavirus replication is controlled by the viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme, which is required for the virus's life cycle. In the cases of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV), 3CLpro has been shown to be a promising therapeutic development target. Here we proposed an attention-based deep learning framework for molecular graphs and sequences, training from the BindingDB 3CLpro dataset (114,555 compounds). After construction of such model, we conducted large-scale screening the in vivo/vitro dataset (276,003 compounds) from Zinc Database and visualize the candidate compounds with attention score. geometric-based affinity prediction was employed for validation. Finally, we established a 3CLpro-specific deep learning framework, namely GraphDPI-3CL (AUROC: 0.958) achieved superior performance beyond the existing state of the art model and discovered 10 molecules with a high binding affinity of 3CLpro and superior binding mode.
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Antivirais , Tratamento Farmacológico da COVID-19 , Aprendizado Profundo , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/antagonistas & inibidores , Ligação Proteica , COVID-19/virologia , Simulação de Acoplamento MolecularRESUMO
The use of metaphors to talk about cancer experiences has attracted much research and debate, especially in the case of military metaphors. However, questions remain about what metaphors are used by different populations for different aspects of the cancer experience. This scoping review aims to answer them.We searched PubMed, PsycINFO, CINAHL, Scopus and Web of Science databases. Eligible sources include peer-reviewed scientific research published in English between 2013 and 2023, investigating patterns of metaphor use from adult populations (age ≥18) for cancer-related topics, such as cancer itself, the general experience of being ill, treatment, and people and relationships.Out of 1929 articles identified, 30 met the criteria, spanning over different populations. While most papers focused on cancer in general, some focused on specific cancer types, such as breast cancer. Both spontaneous and elicited data were collected in ten languages: mostly English (N=12), Swedish (N=3) and Arabic (N=3). The identified metaphors were subsumed under various broad categories, including particularly violence and journey. Other categories include education and non-human animate entity for the cancer itself, confinement and deprivation and cleanliness for the general experience of being ill with cancer, Poison and gardening for cancer treatment, and distance for patients' social relationships.It was found that metaphors help to identify how patients describe experiences of vulnerability and empowerment. To provide patient-centred care, clinicians and researchers should avoid blanket conclusions about helpful or unhelpful metaphors, but consider the ways in which different metaphors are used by different populations in different contexts.
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Extracellular vesicles (EVs) in urine are a promising source for developing non-invasive biomarkers. However, urine concentration and content are highly variable and dynamic, and actual urine collection and handling often is nonideal. Furthermore, patients such as those with prostate diseases have challenges in sample collection due to difficulties in holding urine at designated time points. Here, we simulated the actual situation of clinical sample collection to examine the stability of EVs in urine under different circumstances, including urine collection time and temporary storage temperature, as well as daily urine sampling under different diet conditions. EVs were isolated using functionalized EVtrap magnetic beads and characterized by nanoparticle tracking analysis (NTA), western blotting, electron microscopy, and mass spectrometry (MS). EVs in urine remained relatively stable during temporary storage for 6 hours at room temperature and for 12 hours at 4 °C, while significant fluctuations were observed in EV amounts from urine samples collected at different time points from the same individuals, especially under certain diets. Sample normalization with creatinine reduced the coefficient of variation (CV) values among EV samples from 17% to approximately 6% and facilitated downstream MS analyses. Finally, based on the results, we applied them to evaluate potential biomarker panels in prostate cancer by data-independent acquisition (DIA) MS, presenting the recommendation that can facilitate biomarker discovery with nonideal handling conditions.
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Vesículas Extracelulares , Neoplasias da Próstata , Proteômica , Coleta de Urina , Humanos , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Coleta de Urina/métodos , Masculino , Proteômica/métodos , Neoplasias da Próstata/urina , Espectrometria de Massas/métodos , Biomarcadores/urina , TemperaturaRESUMO
OBJECTIVE: To explore the clinical features and genetic etiology of a child with Central core disease (CCD). METHODS: A child with CCD who was treated at the Children's Hematology Department of the First Affiliated Hospital of Zhengzhou University in February 2022 was selected as the study subject. Muscle biopsy was performed. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. RESULTS: The child, a 12-year-old boy, had manifested motor retardation, facial weakness, ptosis, pectus carinatum, scoliosis, etc. Muscle biopsy showed that the central nucleus muscle fibers and atrophic muscle fibers were mainly type I. WES revealed that the child has harbored c.10561G>A (p.G3521S) and c.3448T>C (p.C1150R) compound heterozygous variants of the RYR1 gene. Sanger sequencing confirmed that they were inherited from his mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were considered as likely pathogenic (PS4+PM1+PM2_Supporting+PP3ï¼PM1+PM2_Supporting+PM3+PP3). CONCLUSION: By combining his clinical manifestation and results of muscle pathology and genetic testing, the child was diagnosed with CCD, which may be attributed to the c.10561G>A (p.G3521S) and c.3448T>C (p.C1150R) compound heterozygous variants of the RYR1 gene.
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Heterozigoto , Miopatia da Parte Central , Canal de Liberação de Cálcio do Receptor de Rianodina , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Masculino , Criança , Miopatia da Parte Central/genética , Sequenciamento do Exoma , Mutação , Testes GenéticosRESUMO
Osteoarthritis (OA) is the most prevalent degenerative cartilage disease, but no effective treatment is currently available to ameliorate the dysregulation of cartilage catabolism. Cartilage degeneration is closely related to the change in the physiology of chondrocytes: for example, chondrocytes of the OA patients overexpress matrix metallopeptidase 13 (MMP13), a.k.a. collagenase 3, which damages the extracellular matrix (ECM) of the cartilage and deteriorate the disease progression. Inhibiting MMP13 has shown to be beneficial for OA treatments, but delivering therapeutics to the chondrocytes embedded in the dense cartilage is a challenge. Here, we engineered the exosome surface with the cartilage affinity peptide (CAP) through lipid insertion to give chondrocyte-targeting exosomes, CAP-Exo, which was then loaded with siRNA against MMP13 (siMMP13) in the interior to give CAP-Exo/siMMP13. Intra-articular administration of CAP-Exo/siMMP13 reduced the MMP13 level and increased collagen COL2A1 and proteoglycan in cartilage in a rat model of anterior cruciate ligament transection (ACLT)-induced OA. Proteomic analysis showed that CAP-Exo/siMMP13 treatment restored the altered protein levels in the IL-1ß-treated chondrocytes. Taken together, a facile exosome engineering method enabled targeted delivery of siRNA to chondrocytes and chondrocyte-specific silencing of MMP13 to attenuate cartilage degeneration.
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Condrócitos , Exossomos , Metaloproteinase 13 da Matriz , Osteoartrite , RNA Interferente Pequeno , Ratos Sprague-Dawley , Regeneração , Exossomos/metabolismo , Animais , Condrócitos/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/genética , RNA Interferente Pequeno/administração & dosagem , Osteoartrite/terapia , Masculino , Cartilagem Articular/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Células Cultivadas , Humanos , Ratos , Cartilagem/metabolismoRESUMO
BACKGROUND: Programmed cell death 1 (PD-1) inhibitors can induce various adverse reactions associated with immunity, of which cardiotoxicity is a serious complication. Limited research exists on the link between PD-1 inhibitor use and pericardial effusion (PE) occurrence and outcomes. METHODS: We conducted a retrospective study at the First Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2019, comparing cancer patients who developed PE within 2 years after PD-1 inhibitor therapy to those who did not. Our primary outcome was the all-cause mortality rate at one year. We applied the Kaplan-Meier method for survival analysis. Multivariate logistic regression was utilized to identify PE risk factors, adjusting for potential confounders. RESULTS: A total of 91 patients were finally included, of whom 39 patients had PE. Compared to non-PE group, one-year all-cause mortality was nearly 5 times higher in PE group (64.10% vs. 13.46%, P < 0.001). Patients who developed PE within 2 years of taking PD-1 inhibitors were significantly associated with increased all-cause mortality compared with those who did not (HR: 6.26, 95%CI: 2.70-14.53, P < 0.001). Multivariable logistic regression showed that use of sintilimab (OR: 14.568, 95%CI: 3.431-61.857, P < 0.001), history of lung cancer (OR: 15.360, 95%CI: 3.276-72.017, P = 0.001), and history of hypocalcemia (OR: 7.076, 95%CI: 1.879-26.649, P = 0.004) were independent risk factors of PE development in patients received PD-1 inhibitors therapy. CONCLUSIONS: In cancer patients receiving PD-1 inhibitors, PE was associated with higher one-year mortality. Use of sintilimab, and history of lung cancer or hypocalcemia were linked to PE occurrence.
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Inibidores de Checkpoint Imunológico , Neoplasias , Derrame Pericárdico , Humanos , Derrame Pericárdico/epidemiologia , Derrame Pericárdico/induzido quimicamente , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Idoso , Inibidores de Checkpoint Imunológico/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
Theaflavins are beneficial to human health due to various bioactivities. Biosynthesis of theaflavins using polyphenol oxidase (PPO) is advantageous due to cost effectiveness and environmental friendliness. In this review, studies on the mechanism of theaflavins formation, the procedures to screen and prepare PPOs, optimization of reaction systems and immobilization of PPOs were described. The challenges associated with the mass biosynthesis of theaflavins, such as poor enzyme activity, undesirable subproducts and inclusion bodies of recombinant PPOs were presented. Further strategies to solve these challenges and improve theaflavins production, including enzyme engineering, immobilization enzyme technology, water-immiscible solvent-water biphasic systems and recombinant enzyme technology, were proposed.
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Biflavonoides , Catequina , Catecol Oxidase , Biflavonoides/química , Biflavonoides/metabolismo , Biocatálise , Catequina/química , Catequina/metabolismo , Catecol Oxidase/metabolismo , Catecol Oxidase/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismoRESUMO
APE1 is an essential gene involved in DNA damage repair, the redox regulation of transcriptional factors (TFs) and RNA processing. APE1 overexpression is common in cancers and correlates with poor patient survival. Stress granules (SGs) are phase-separated cytoplasmic assemblies that cells form in response to environmental stresses. Precise regulation of SGs is pivotal to cell survival, whereas their dysregulation is increasingly linked to diseases. Whether APE1 engages in modulating SG dynamics is worthy of investigation. In this study, we demonstrate that APE1 colocalizes with SGs and promotes their formation. Through phosphoproteome profiling, we discover that APE1 significantly alters the phosphorylation landscape of ovarian cancer cells, particularly the phosphoprofile of SG proteins. Notably, APE1 promotes the phosphorylation of Y-Box binding protein 1 (YBX1) at S174 and S176, leading to enhanced SG formation and cell survival. Moreover, expression of the phosphomutant YBX1 S174/176E mimicking hyperphosphorylation in APE1-knockdown cells recovered the impaired SG formation. These findings shed light on the functional importance of APE1 in SG regulation and highlight the importance of YBX1 phosphorylation in SG dynamics.
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DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Neoplasias Ovarianas , Grânulos de Estresse , Proteína 1 de Ligação a Y-Box , Feminino , Humanos , Endodesoxirribonucleases , Neoplasias Ovarianas/genética , Fosforilação , Grânulos de Estresse/metabolismo , Proteína 1 de Ligação a Y-Box/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismoRESUMO
Docetaxel (DTX) is a semi-synthetic analogue of paclitaxel which has attracted extensive attention in the treatment of cancer. However, the current clinically used DTX formulations display low tumor targeting ability, leading to unsatisfactory therapeutic outcomes with adverse effects, which poses significant challenges to the clinical application. In this study, three galactosamine (Gal) and docetaxel conjugates with different linkers were synthesized, namely DTX-(suc-Gal)2, DTX-(DTDPA-Gal)2, and DTX-(DSeDPA-Gal)2. These three conjugates were characterized by 1H NMR, FT-IR and HRMS. The in vitro drug release study shows that DTX-(DTDPA-Gal)2 and DTX-(DSeDPA-Gal)2 exhibit glutathione (GSH)-responsive drug release and DTX-(DSeDPA-Gal)2 displays higher GSH-responsiveness. The in vitro antitumor activity study shows that DTX-(DTDPA-Gal)2 and DTX-(DSeDPA-Gal)2 exhibit enhanced cytotoxicity, cell apoptosis rate and G2/M phase arrest against HepG2 cells as compared to DTX-(suc-Gal)2, DTX-(DSeDPA-Gal)2 displays the highest cytotoxicity, cell apoptosis rate and G2/M phase arrest among these three conjugates. In addition, DTX-(DSeDPA-Gal)2 exhibits higher selectivity to HepG2 cells as compared to free DTX. The DTX-(DSeDPA-Gal)2 developed in this study has been proven to be an effective DTX conjugate for selective killing hepatoma cells.
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Antineoplásicos , Docetaxel/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Galactosamina , Espectroscopia de Infravermelho com Transformada de Fourier , Taxoides/farmacologia , Taxoides/química , Portadores de Fármacos/química , Linhagem Celular TumoralRESUMO
BRAF mutations are found in 1-5% of non-small-cell lung cancer (NSCLC), with V600 and non-V600 accounting for approximately 50% each. It has been confirmed that targeted therapy with dabrafenib + trametinib is effective in patients with metastatic NSCLC carrying BRAF V600E mutations. Preclinical studies have shown that dabrafenib + trametinib may also have inhibitory effects on some types of non-V600E mutations, especially some class II BRAF mutations. However, the efficacy of dabrafenib + trametinib on non-V600E mutant NSCLC in clinical practice only exists in some case reports. Here, we report a case of NSCLC patient carrying BRAF ex15 p.T599dup, who showed a clinical response to the combined therapy of dabrafenib + trametinib.
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Carcinoma Pulmonar de Células não Pequenas , Imidazóis , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Oximas/uso terapêutico , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/uso terapêuticoRESUMO
Ube3a is a member of the E3 ubiquitin ligase HECTc family, and its role has been established in neurodevelopmental disorders. However, studies on its role in Japanese flounder are scarce. Thus, in this study, the ube3a of Japanese flounder was cloned, and its role in conferring resistance against Chinook salmon bafnivirus (CSBV) was analyzed. Japanese flounder ube3a encoded a protein containing 834 amino acids. Interestingly, its homology with the Atlantic halibut was determined to be 94%. In addition, there were differential expressions of ube3a in different tissues of Japanese flounder, with the highest expression level observed in the fin, followed by the gills and skin (P ≤ 0.05). Subcellular localization analysis revealed that Ube3a is a cytoplasmic protein. We established an in vitro CSBV infection model using Japanese flounder gill cell line (FG). After ube3a overexpression, the viral load was significantly lower than that of the control group (P ≤ 0.05). Contrastingly, after incubation of FG cells with an E3 ubiquitin ligase inhibitor, the viral load was significantly higher than in the control group (P ≤ 0.01). Then, the expression levels of nf-κb, traf3, and tnf-α after incubation with an E3 ubiquitin ligase inhibitor were examined. The results demonstrated that ube3a may exerted a significant antiviral effect in Japanese flounder via the ubiquitination pathway.