RESUMO
Periodontitis is a chronic inflammatory disease that affects about 45 %-50 % of adults worldwide, but the efficacy of current clinical therapies is unsatisfactory due to the complicated periodontal immune microenvironment. Thus, developing drugs that can regulate innate immune cells (e.g., macrophages) is a potent strategy to treat periodontitis. Here, we report that phloretin, a food plant-derived natural compound, is sufficient to alleviate periodontitis through immune regulation. In vivo, phloretin treatment could significantly reduce alveolar bone resorption and periodontal inflammation in mouse periodontitis models. In vitro, phloretin could suppress proinflammatory (M1-like) polarization and cytokine release in macrophages induced by LPS. Mechanistically, the immune regulatory role of phloretin in macrophages may be due to its metabolic regulation effect. Phloretin might restore the balance of M1/M2 macrophage transition in periodontitis by inhibiting HIF-1α-mediated glycolysis and PI3k/Akt pathways, thereby reducing the proinflammatory effect and immune disorder caused by over-activated M1 macrophages. Together, this study highlights that natural compound, such as phloretin, can restore periodontal immune homeostasis by metabolic regulation of macrophages, which may provide novel insight into the treatment of periodontitis.
Assuntos
Glicólise , Homeostase , Subunidade alfa do Fator 1 Induzível por Hipóxia , Macrófagos , Camundongos Endogâmicos C57BL , Periodontite , Floretina , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Floretina/farmacologia , Floretina/uso terapêutico , Glicólise/efeitos dos fármacos , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Periodontite/tratamento farmacológico , Periodontite/imunologia , Periodontite/metabolismo , Homeostase/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Masculino , Lipopolissacarídeos/imunologia , Humanos , Células RAW 264.7 , Modelos Animais de Doenças , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Perda do Osso Alveolar/tratamento farmacológicoRESUMO
OBJECTIVE: To extract texture features from vocal cord leukoplakia (VCL) images and establish a VCL risk stratification prediction model using machine learning (ML) techniques. METHODS: A total of 462 patients with pathologically confirmed VCL were retrospectively collected and divided into low-risk and high-risk groups. We use a 5-fold cross validation method to ensure the generalization ability of the model built using the included dataset and avoid overfitting. Totally 504 texture features were extracted from each laryngoscope image. After feature selection, 10 ML classifiers were utilized to construct the model. The SHapley Additive exPlanations (SHAP) was employed for feature analysis. To evaluate the model, accuracy, sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) were utilized. In addition, the model was transformed into an online application for public use and further tested in an independent dataset with 52 cases of VCL. RESULTS: A total of 12 features were finally selected, random forest (RF) achieved the best model performance, the mean accuracy, sensitivity, specificity, and AUC of the 5-fold cross validation were 92.2 ± 4.1%, 95.6 ± 4.0%, 85.8 ± 5.8%, and 90.7 ± 4.9%, respectively. The result is much higher than the clinicians (AUC between 63.1% and 75.2%). The SHAP algorithm ranks the importance of 12 texture features to the model. The test results of the additional independent datasets were 92.3%, 95.7%, 90.0%, and 93.3%, respectively. CONCLUSION: The proposed VCL risk stratification prediction model, which has been developed into a public online prediction platform, may be applied in practical clinical work. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:4329-4337, 2024.
Assuntos
Leucoplasia , Aprendizado de Máquina , Prega Vocal , Humanos , Prega Vocal/patologia , Medição de Risco/métodos , Masculino , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Leucoplasia/patologia , Laringoscopia/métodos , Idoso , Curva ROC , Adulto , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Rising prostate-specific antigen (PSA) levels following radical prostatectomy are indicative of a poor prognosis, which may associate with periprostatic adipose tissue (PPAT). Accordingly, we aimed to construct a dynamic online nomogram to predict tumor short-term prognosis based on 18F-PSMA-1007 PET/CT of PPAT. METHODS: Data from 268 prostate cancer (PCa) patients who underwent 18F-PSMA-1007 PET/CT before prostatectomy were analyzed retrospectively for model construction and validation (training cohort: n = 156; internal validation cohort: n = 65; external validation cohort: n = 47). Radiomics features (RFs) from PET and CT were extracted. Then, the Rad-score was constructed using logistic regression analysis based on the 25 optimal RFs selected through maximal relevance and minimal redundancy, as well as the least absolute shrinkage and selection operator. A nomogram was constructed to predict short-term prognosis which determined by persistent PSA. RESULTS: The Rad-score consisting of 25 RFs showed good discrimination for classifying persistent PSA in all cohorts (all P < 0.05). Based on the logistic analysis, the radiomics-clinical combined model, which contained the optimal RFs and the predictive clinical variables, demonstrated optimal performance at an AUC of 0.85 (95% CI: 0.78-0.91), 0.77 (95% CI: 0.62-0.91) and 0.84 (95% CI: 0.70-0.93) in the training, internal validation and external validation cohorts. In all cohorts, the calibration curve was well-calibrated. Analysis of decision curves revealed greater clinical utility for the radiomics-clinical combined nomogram. CONCLUSION: The radiomics-clinical combined nomogram serves as a novel tool for preoperative individualized prediction of short-term prognosis among PCa patients.
Assuntos
Tecido Adiposo , Nomogramas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Retrospectivos , Prognóstico , Tecido Adiposo/diagnóstico por imagem , Pessoa de Meia-Idade , Idoso , Compostos Radiofarmacêuticos , Prostatectomia , Oligopeptídeos , Valor Preditivo dos Testes , Niacinamida/análogos & derivadosRESUMO
Despite the fact that lower back pain caused by degenerative lumbar spine pathologies seriously affects the quality of life, however, there is a paucity of research on the biomechanical properties of different auxiliary fixation systems for its primary treatment (oblique lumbar interbody fusion) under vibratory environments. In order to study the effects of different fixation systems of OLIF surgery on the vibration characteristics of the human lumbar spine under whole-body vibration (WBV), a finite element (FE) model of OLIF surgery with five different fixation systems was established by modifying a previously established model of the normal lumbar spine (L1-S1). In this study, a compressive follower load of 500 N and a sinusoidal axial vertical load of ±40 N at the frequency of 5 Hz with a duration of 0.6 s was applied. The results showed that the bilateral pedicle screw fixation model had the highest resistance to cage subsidence and maintenance of disc height under WBV. In contrast, the lateral plate fixation model exerted very high stresses on important tissues, which would be detrimental to the patient's late recovery and reduction of complications. Therefore, this study suggests that drivers and related practitioners who are often in vibrating environments should have bilateral pedicle screws for OLIF surgery, and side plates are not recommended to be used as a separate immobilization system. Additionally, the lateral plate is not recommended to be used as a separate fixation system.
Assuntos
Análise de Elementos Finitos , Vértebras Lombares , Fusão Vertebral , Vibração , Fusão Vertebral/instrumentação , Vértebras Lombares/cirurgia , Humanos , Fenômenos Biomecânicos , Parafusos PedicularesRESUMO
PURPOSE: Biochemical recurrence (BCR) following radical prostatectomy (RP) is a significant concern for patients with prostate cancer. Reliable prediction models are needed to identify patients at risk for BCR and facilitate appropriate management. This study aimed to develop and validate a clinical-radiomics model based on preoperative [18 F]PSMA-1007 PET for predicting BCR-free survival (BRFS) in patients who underwent RP for prostate cancer. MATERIALS AND METHODS: A total of 236 patients with histologically confirmed prostate cancer who underwent RP were retrospectively analyzed. All patients had a preoperative [18 F]PSMA-1007 PET/CT scan. Radiomics features were extracted from the primary tumor region on PET images. A radiomics signature was developed using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The performance of the radiomics signature in predicting BRFS was assessed using Harrell's concordance index (C-index). The clinical-radiomics nomogram was constructed using the radiomics signature and clinical features. The model was externally validated in an independent cohort of 98 patients. RESULTS: The radiomics signature comprised three features and demonstrated a C-index of 0.76 (95% CI: 0.60-0.91) in the training cohort and 0.71 (95% CI: 0.63-0.79) in the validation cohort. The radiomics signature remained an independent predictor of BRFS in multivariable analysis (HR: 2.48, 95% CI: 1.47-4.17, p < 0.001). The clinical-radiomics nomogram significantly improved the prediction performance (C-index: 0.81, 95% CI: 0.66-0.95, p = 0.007) in the training cohort and (C-index: 0.78 95% CI: 0.63-0.89, p < 0.001) in the validation cohort. CONCLUSION: We developed and validated a novel [18 F]PSMA-1007 PET-based clinical-radiomics model that can predict BRFS following RP in prostate cancer patients. This model may be useful in identifying patients with a higher risk of BCR, thus enabling personalized risk stratification and tailored management strategies.
Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Oligopeptídeos/química , Intervalo Livre de Doença , Processamento de Imagem Assistida por Computador , Radiômica , Niacinamida/análogos & derivadosRESUMO
Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1-10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.
Assuntos
Antineoplásicos , Receptores Frizzled , Neoplasias , Via de Sinalização Wnt , Humanos , Receptores Frizzled/metabolismo , Receptores Frizzled/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , Terapia de Alvo Molecular/métodosRESUMO
BACKGROUND: In Total Hip replacement (THR) surgery, a critical step is to cut an accurate hemisphere into the acetabulum so that the component can be fitted accurately and obtain early stability. This study aims to determine whether burring rather than reaming the acetabulum can achieve greater accuracy in the creation of this hemisphere. METHODS: A preliminary robotic system was developed to demonstrate the feasibility of burring the acetabulum using the Universal Robot (UR10). The study will describe mechanical design, robot trajectory optimisation, control algorithm development, and results from phantom experiments compared with both robotic reaming and conventional reaming. The system was also tested in a cadaver experiment. RESULTS: The proposed robotic burring system can produce a surface in 2 min with an average error of 0.1 and 0.18 mm, when cutting polyurethane bone block #15 and #30, respectively. The performance was better than robotic reaming and conventional hand reaming. CONCLUSION: The proposed robotic burring system outperformed robotic and conventional reaming methods to produce an accurate acetabular cavity. The findings show the potential usage of a robotic-assisted burring in THR for acetabular preparation.
Assuntos
Artroplastia de Quadril , Prótese de Quadril , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Acetábulo/cirurgia , Artroplastia de Quadril/métodosRESUMO
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of dormant JC polyomavirus (JCPyV). PML was mainly observed in immunocompromised individuals, such as HIV-positive patients, autoimmune disease patients, and cancer patients. Given that the presence of anti-JCPyV antibodies in serum is a risk indicator for PML development, it is essential to monitor anti-JCPyV antibody levels. In the present study, we established reporter-based single-infection neutralization assays for JCPyV and the genetically similar BK polyoma virus (BKPyV). We then confirmed the lack of cross-reactivity between the two viruses using test sera obtained from mice immunized with plasmids encoding the JCPyV or BKPyV capsid. Next, we compared neutralization antibody titers in sera from healthy donors, patients with multiple sclerosis (MS), and HIV-positive patients using an in-house enzyme-linked immunosorbent assay (ELISA) with JCPyV-like particles (virus-like particles; VLPs). A positive correlation was demonstrated between the neutralization titer (75% infectious concentration; IC75) against JCPyV and the antibody titer obtained by VLP-based JCPyV ELISA. This assay system may be applied to detect antibodies against other PyVs by generation of pseudoviruses using the respective capsid expression plasmids, and is expected to contribute to the surveillance of PyV as well as basic research on these viruses.
RESUMO
Orthodontic tooth movement (OTM) is a highly coordinated biomechanical response to orthodontic forces with active remodelling of alveolar bone but minor root resorption. Such antiresorptive properties of root relate to cementocyte mineralization, the mechanisms of which remain largely unknown. This study used the microarray analysis to explore long non-coding ribonucleic acids involved in stress-induced cementocyte mineralization. Gain- and loss-of-function experiments, including Alkaline phosphatase (ALP) activity and Alizarin Red S staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence analyses of mineralization-associated factors, were conducted to verify long non-coding ribonucleic acids taurine-upregulated gene 1 (LncTUG1) regulation in stress-induced cementocyte mineralization, via targeting the Toll-like receptor 4 (TLR4)/SphK1 axis. The luciferase reporter assays, chromatin immunoprecipitation assays, RNA pull-down, RNA immunoprecipitation, and co-localization assays were performed to elucidate the interactions between LncTUG1, PU.1, and TLR4. Our findings indicated that LncTUG1 overexpression attenuated stress-induced cementocyte mineralization, while blocking the TLR4/SphK1 axis reversed the inhibitory effect of LncTUG1 on stress-induced cementocyte mineralization. The in vivo findings also confirmed the involvement of TLR4/SphK1 signalling in cementocyte mineralization during OTM. Mechanistically, LncTUG1 bound with PU.1 subsequently enhanced TLR4 promotor activity and thus transcriptionally elevated the expression of TLR4. In conclusion, our data revealed a critical role of LncTUG1 in regulating stress-induced cementocyte mineralization via PU.1/TLR4/SphK1 signalling, which might provide further insights for developing novel therapeutic strategies that could protect roots from resorption during OTM.
Assuntos
Proteínas Proto-Oncogênicas , RNA Longo não Codificante , Transdução de Sinais , Receptor 4 Toll-Like , Transativadores , Animais , Camundongos , Calcificação Fisiológica/genética , Cemento Dentário/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptor 4 Toll-Like/metabolismo , Técnicas de Movimentação Dentária , Transativadores/metabolismo , Transativadores/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismoRESUMO
OBJECTIVE: Currently, there are few practical tools for predicting the prognosis of laryngeal squamous cell carcinoma (LSCC). This study aims to establish a model and a convenient online prediction platform to predict whether LSCC patients will survive 5 years after diagnosis, providing a reference for further evaluation of patient prognosis. METHODS: This is a retrospective study based on data collected from two centers. Center 1 included 117 LSCC patients with survival prognosis data, and center 2 included 33 patients, totaling 150 patients. All data were divided into independent training sets (60 %) and testing sets (40 %). Eight machine learning (ML) algorithms were used to establish models with 11 clinical parameters as input features. The accuracy, sensitivity, specificity, and receiver operating characteristic curve (ROC) of the testing set were used to evaluate the models, and the best model was selected. The model was then developed into a website-based 5-year survival status prediction platform for LSCC. In addition, we also used the SHapley Additive exPlanations (SHAP) tool to conduct interpretability analysis on the parameters of the model. RESULTS: The LSCC 5-year survival status prediction model using the support vector machine (SVM) algorithm achieved the best results, with accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of 85.0 %, 87.5 %, 75.0 %, and 81.2 % respectively. The online platform for predicting the 5-year survival status of LSCC based on this model was successfully established. The SHAP analysis shows that the clinical stage is the most important feature of the model. CONCLUSION: This study successfully established a ML model and a practical online prediction platform to predict the survival status of laryngeal cancer patients after 5 years, which may help clinicians to better evaluate the prognosis of LSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Laríngeas , Humanos , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/diagnóstico , Masculino , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Prognóstico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Taxa de Sobrevida , Idoso , Aprendizado de Máquina , Fatores de Tempo , Algoritmos , Curva ROC , Máquina de Vetores de Suporte , Valor Preditivo dos Testes , InternetRESUMO
OBJECTIVE: We developed a novel method for thyroidectomy using a single-incision oral vestibular approach. To assess its advantages and disadvantages, we compared the perioperative parameters of this approach with those of transoral three-incision thyroidectomy and trans-areolar thyroidectomy. METHODS: In a study of 136 papillary thyroid carcinoma patients (2016-2018), precise thyroidectomy and neck dissection were conducted. Among them, 52 chose single-incision oral vestibular approach, 33 chose three-incision variant, and 51 underwent trans-areolar thyroidectomy. Perioperative aspects of the transoral single-incision group were compared with those of transoral three-incision group, and transthoracic group. RESULTS: In the cohort, meticulous tumor level VI lymph node dissection was performed, achieving intended resection extent with one case requiring a switch from transoral to transthoracic approach. No nerve palsy occurred in the transoral group. Thyroidectomy duration varied significantly across groups. Transoral single-incision had a shorter duration than transoral three-incision and longer than transthoracic. Minor differences were observed in blood loss and drainage. Perioperative factors like hematoma, infection, hypocalcemia, et al., remained consistent. Notably, no tumor recurrence was observed in this study. CONCLUSIONS: This new transoral video-assisted neck surgery (TOVANS) method for thyroidectomy without gas insufflation approach did not increase the surgical complexity compared with the transoral vestibular three-incision thyroidectomy and the trans-areolar thyroidectomy. LEVEL OF EVIDENCE: 3 Laryngoscope, 2023.
RESUMO
Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell-mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell-dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.
Assuntos
Carcinógenos , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Carcinógenos/toxicidade , Microambiente Tumoral , Linfócitos T , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/metabolismo , Imunoterapia/métodosRESUMO
A Japanese rabbit hepatitis E virus (HEV) strain, JP-59, has been identified in a feral rabbit. When this virus was transmitted to a Japanese white rabbit, it caused persistent HEV infection. The JP-59 strain shares an <87.5% nucleotide sequence identity with other rabbit HEV strains. Herein, to isolate JP-59 by cell culture, we used a 10% stool suspension recovered from a JP-59-infected Japanese white rabbit and contained 1.1 × 107 copies/mL of the viral RNA and using it to infect a human hepatocarcinoma cell line, PLC/PRF/5. No sign of virus replication was observed. Although long-term virus replication was observed in PLC/PRF/5 cells inoculated with the concentrated and purified JP-59 containing a high titer of viral RNA (5.1 × 108 copies/mL), the viral RNA of JP-59c that was recovered from the cell culture supernatants was <7.1 × 104 copies/mL during the experiment. The JP-59c strain did not infect PLC/PRF/5 cells, but its intravenous inoculation caused persistent infection in rabbits. The nucleotide sequence analyses of the virus genomes demonstrated that a total of 18 nucleotide changes accompanying three amino acid mutations occurred in the strain JP-59c compared to the original strain JP-59. These results indicate that a high viral RNA titer was required for JP-59 to infect PLC/PRF/5 cells, but its replication capability was extremely low. In addition, the ability of rabbit HEVs to multiply in PLC/PRF/5 cells varied depending on the rabbit HEV strains. The investigations of cell lines that are broadly susceptible to rabbit HEV and that allow the efficient propagation of the virus are thus needed.
Assuntos
Vírus da Hepatite E , Cultura de Vírus , Replicação Viral , Animais , Humanos , Coelhos , Hepatite E/veterinária , Vírus da Hepatite E/fisiologia , RNA Viral/genética , RNA Viral/análise , Linhagem Celular TumoralRESUMO
The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC.
Assuntos
Antineoplásicos , Neoplasias , Quimera de Direcionamento de Proteólise , Animais , Humanos , Camundongos , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Mutação , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Fator de Transcrição AP-1 , Quimera de Direcionamento de Proteólise/química , Quimera de Direcionamento de Proteólise/farmacologiaRESUMO
OBJECTIVE: Delayed regeneration of alveolar bone defects because of prolonged inflammation under diabetic conditions remains a challenge for dental rehabilitation in clinic, and effective therapies are required. Cytokines-based immuotherapies might be a potential strategy to regulate inflammation and bone regeneration. Here, we report that local delivery of interleukin-10 (IL-10) by injectable self-assembling peptide (SAP) hydrogel is efficient to promote proinflammatory (M1)-to-anti-inflammatory (M2) phenotype conversion, thereby enhancing bone regeneration in diabetic alveolar bone defects. METHODS: Characteristics of SAP hydrogel were evaluated by morphology, injectable and rheological properties. The loading and release of IL-10 from the SAP hydrogel were evaluated over time in culture. The local inflammatory response and bone repair efficacy of the SAP/IL-10 hydrogel was evaluated in vivo using an alveolar bone defect model of diabetic mice. Finally, the direct effects of M2 macrophage on M1 phenotype and mineralization of MSCs were investigated. RESULTS: In vitro, encapsulated IL-10 could be sustainedly released by SAP hydrogel with preserved bioactivities. In vivo, SAP/IL-10 hydrogel showed significantly higher efficacy to attenuate M1 polarization and proinflammatory factors levels, and enhance expressions of osteogenic factors. As a result, diabetic bone regeneration induced by SAP/IL-10 hydrogel was significantly faster. Mechanistically, M2 macrophages induced by sustained IL-10 delivery might promote diabetic bone regeneration by reprogramming M1 phenotype, suppressing local inflammation and enhancing the osteogenic differentiation of mesenchymal stem cells (MSCs). SIGNIFICANCE: This study highlights that the SAP hydrogel is a promising drug delivery platform for treatment of alveolar bone defects, which might have translational potential in future clinical applications.
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Diabetes Mellitus Experimental , Hidrogéis , Ratos , Camundongos , Animais , Hidrogéis/química , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Osteogênese , Diabetes Mellitus Experimental/metabolismo , Ratos Sprague-Dawley , Macrófagos/metabolismo , Peptídeos/metabolismo , Inflamação/metabolismoRESUMO
Although medical science has been fully developed, due to the high heterogeneity of triple-negative breast cancer (TNBC), it is still difficult to use reasonable and precise treatment. In this study, based on local optimization-feature screening and genomics screening strategy, we screened 25 feature genes. In multiple machine learning algorithms, feature genes have excellent discriminative diagnostic performance among samples composed of multiple large datasets. After screening at the single-cell level, we identified genes expressed substantially in myeloid cells (MCGs) that have a potential association with TNBC. Based on MCGs, we distinguished two types of TNBC patients who showed considerable differences in survival status and immune-related characteristics. Immune-related gene risk scores (IRGRS) were established, and their validity was verified using validation cohorts. A total of 25 feature genes were obtained, among which CXCL9, CXCL10, CCL7, SPHK1, and TREM1 were identified as the result after single-cell level analysis and screening. According to these entries, the cohort was divided into MCA and MCB subtypes, and the two subtypes had significant differences in survival status and tumor-immune microenvironment. After Lasso-Cox screening, IDO1, GNLY, IRF1, CTLA4, and CXCR6 were selected for constructing IRGRS. There were significant differences in drug sensitivity and immunotherapy sensitivity among high-IRGRS and low-IRGRS groups. We revealed the dynamic relationship between TNBC and TIME, identified a potential biomarker called Granulysin (GNLY) related to immunity, and developed a multi-process machine learning package called "MPMLearning 1.0" in Python.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Algoritmos , Genômica , Aprendizado de Máquina , Microambiente TumoralRESUMO
OBJECTIVES: Gallium-68 (68Ga)-labeled somatostatin analog (SSA) PET imaging has been widely used in clinical practice of neuroendocrine neoplasms (NENs). Compared with 68Ga, 18F has a great practical and economic advantage. Although a few studies have shown the characteristics of [18F] AlF-NOTA-octreotide ([18F]-OC) in healthy volunteers and small NEN patient groups, its clinical value needs further investigation. Herein, this retrospective study aimed to evaluate the diagnostic accuracy of [18F]-OC PET/CT in detecting NENs, as well as to compare it with contrast-enhanced CT/MRI. METHODS: We retrospectively reviewed the data of 93 patients who had undergone [18F]-OC PET/CT and CT or MRI scans. Of these patients, there were 45 patients with suspected NENs for diagnostic evaluation, and 48 patients with pathologically confirmed NENs for detecting metastasis or recurrence. [18F]-OC PET/CT images were evaluated visually and semi-quantitatively by measuring maximum standardized uptake value of tumor (SUVmax), tumor-to-background SUVmax ratio (TBR), and SUVmax of hypophysis (SUVhypophysis). A total of 276 suspected NEN lesions were found in these 93 patients. The results of histopathology or radiographic follow-up served as the reference standard for the final diagnosis. RESULTS: Forty-five patients with suspected NENs were confirmed by histopathological examination via resection or biopsy. [18F]-OC PET/CT showed high radiotracer uptake in the lesions of G1-G3 NENs. [18F]-OC PET/CT showed superior performance with 96.3% of sensitivity, 77.8% of specificity, and 88.9% of accuracy in diagnosing NENs compared to CT/MRI. When cutoffs of SUVmax, TBR, and SUVhypophysis were 8.3, 3.1, and 15.4, [18F]-OC PET/CT had the best equilibrium between sensitivity and specificity for differentiating NEN from non-NEN lesions. For a total of 276 suspected NEN lesions, the sensitivity, specificity, and accuracy of [18F]-OC PET/CT for diagnosis of NENs were 90.5%, 82.1%, and 88.8%, respectively, and were higher than those of CT and MRI. G1 and G2 NENs had higher TBR and lower CT enhancement intensity than G3. The SUVmax and TBR had a positive correlation with CT enhancement intensity in G2 rather than in G1 or G3. CONCLUSIONS: [18F]-OC PET/CT is a promising imaging modality for initial diagnosis and detecting metastasis or postoperative recurrence in NENs.
Assuntos
Tumores Neuroendócrinos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos de Gálio , Estudos Retrospectivos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Imageamento por Ressonância MagnéticaRESUMO
Objective: Radiofrequency coblation (RFC) is a relatively new method that has opened up new perspectives in treating oropharyngeal squamous cell carcinoma (OPSCC). Our study was designed to explore the feasibility and effectiveness of RFC-assisted transoral surgery (RFC-TOS) for primary OPSCC. Methods: Sixty-nine cases of OPSCC from February 2005 to November 2020 were retrospectively analyzed, including 31 in the RFC-TOS group and 38 in the open surgery group. No difference was observed in demographic and oncological characteristics. Results: The significance between the RFC-TOS group and the open surgery group was proved in intraoperative bleeding volume (34.10 ± 10.10 ml vs. 193.68 ± 21.00 ml, P < 0.001), durations of surgery (79.58 ± 8.45 min vs. 217.87 ± 17.65 min, P < 0.001), time to resume oral feeding (1.64 ± 0.41 d vs. 11.58 ± 1.41 d, P < 0.001), duration of hospitalization (7.84 ± 0.66 d vs. 15.66 ± 1.62 d, P < 0.001), and the total costs (22846.22 ± 1821.55¥ vs. 41792.24 ± 4150.86¥, P < 0.001). The rates of 5-year overall survival (OS), 5-yeardisease-specific survival (DSS), and 5-year local control rate (LC) were 69.1%, 71.7%, and 75.7%, respectively, in the RFC-TOS group and 71.0%, 73.4%, and 73.7% in the open surgery group (P > 0.05). Conclusions: RFC-TOS is a feasible alternative transoral approach for OPSCC. The reported perioperative and oncologic outcomes are satisfactory.
RESUMO
STUDY OBJECTIVES: To investigate the feasibility and effectiveness of nasopharyngeal tube (NPT) insertion in alleviating sleep hypoxemia during the first night after velopharyngeal surgery in patients with obstructive sleep apnea syndrome (OSAS). METHODS: In this prospective nonblinded, randomized, controlled study, 46 patients with obstructive sleep apnea syndrome (OSAS) who underwent velopharyngeal surgery were enrolled and randomly allocated to the control group (with no NPT insertion) and the NPT insertion group. Both groups underwent overnight pulse oximetry tests during the first postoperative night. RESULTS: One patient in the NPT insertion group was excluded because of involuntary self-removal of NPT during sleep. A total of 45 patients with OSAS were included for analysis, with 23 in the control group and 22 in the NPT insertion group. No significant differences in preoperative baseline information were found between the two groups. Compared with the patients in the control group, those patients in the NPT insertion group showed a significantly higher value of the lowest oxygen saturation of oximetry during the first postoperative night (85.0 ± 4.0% vs 79.3 ± 8.0%) (P = .005). The percentage of patients with lowest oxygen saturation of oximetry < 80% in the NPT insertion group was only 9.1% (2 of 22), which was significantly lower than 39.1% (9 of 23) in the control group (P = .035). No patient reported unbearable discomfort related to NPT insertion. The most common mild discomfort was occasional pharyngeal foreign body sensation (6 of 22, 27.3%). CONCLUSIONS: NPT insertion could lessen the severity of sleep hypoxemia during the first night after velopharyngeal surgery in patients with OSAS and showed excellent compliance. This method could be a potential alternative option for decreasing the risks of complications related to severe sleep hypoxemia during the early postoperative days. CITATION: Zhang J, Guan S, Zhang C, Du X, Li T, Xiao S. Nasopharyngeal tube effects on alleviating sleep hypoxemia during the first night following velopharyngeal surgery in patients with obstructive sleep apnea syndrome. J Clin Sleep Med. 2023;19(2):303-308.