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Renal cell carcinoma (RCC) is considered a "metabolic disease" characterized by elevated glycolysis in patients with advanced RCC. Tyrosine kinase inhibitor (TKI) therapy is currently an important treatment option for advanced RCC, but drug resistance may develop in some patients. Combining TKI with targeted metabolic therapy may provide a more effective approach for patients with advanced RCC. An analysis of 14 RCC patients (including three needle biopsy samples with TKI resistance) revealed by sing-cell RNA sequencing (scRNA-seq) that glycolysis played a crucial role in poor prognosis and drug resistance in RCC. TCGA-KIRC and glycolysis gene set analysis identified DEPDC1 as a target associated with malignant progression and drug resistance in KIRC. Subsequent experiments demonstrated that DEPDC1 promoted malignant progression and glycolysis of RCC, and knockdown DEPDC1 could reverse TKI resistance in RCC cell lines. Bulk RNA sequencing (RNA-seq) and non-targeted metabolomics sequencing suggested that DEPDC1 may regulate RCC glycolysis via AKT/mTOR/HIF1α pathway, a finding supported by protein-level analysis. Clinical tissue samples from 98 RCC patients demonstrated that DEPDC1 was associated with poor prognosis and predicted RCC metastasis. In conclusion, this multi-omics analysis suggests that DEPDC1 could serve as a novel target for TKI combined with targeted metabolic therapy in advanced RCC patients with TKI resistance.
Asunto(s)
Carcinoma de Células Renales , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Renales , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Glucólisis/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Línea Celular Tumoral , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Activadoras de GTPasa/genética , Transducción de Señal , Ratones , Animales , Masculino , Femenino , Ratones Desnudos , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Tertiary lymphoid structures (TLSs) serve as organized lymphoid aggregates that influence immune responses within the tumor microenvironment. This study aims to investigate the characteristics and clinical significance of TLSs and tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC). METHODS: TLSs and TILs were analyzed comprehensively in 754 ccRCC patients from 6 academic centers and 532 patients from The Cancer Genome Atlas. Integrated analysis was performed based on single-cell RNA-sequencing datasets from 21 ccRCC patients to investigate TLS heterogeneity in ccRCC. Immunohistochemistry and multiplex immunofluorescence were applied. Cox regression and Kaplan-Meier analyses were used to reveal the prognostic significance. RESULTS: The study demonstrated the existence of TLSs and TILs heterogeneities in the ccRCC microenvironment. TLSs were identified in 16% of the tumor tissues in 113 patients. High density (>0.6/mm2) and maturation of TLSs predicted good overall survival (OS) (p<0.01) in ccRCC patients. However, high infiltration (>151) of scattered TILs was an independent risk factor of poor ccRCC prognosis (HR=14.818, p<0.001). The presence of TLSs was correlated with improved progression-free survival (p=0.002) and responsiveness to therapy (p<0.001). Interestingly, the combination of age and TLSs abundance had an impact on OS (p<0.001). Higher senescence scores were detected in individuals with immature TLSs (p=0.003). CONCLUSIONS: The study revealed the contradictory features of intratumoral TLSs and TILs in the ccRCC microenvironment and their impact on clinical prognosis, suggesting that abundant and mature intratumoral TLSs were associated with decreased risks of postoperative ccRCC relapse and death as well as favorable therapeutic response. Distinct spatial distributions of immune infiltration could reflect effective antitumor or protumor immunity in ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Linfocitos Infiltrantes de Tumor , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Estructuras Linfoides Terciarias/inmunología , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Neoplasias Renales/genética , Femenino , Masculino , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , Pronóstico , Estudios de Cohortes , AncianoRESUMEN
Neoadjuvant tyrosine kinase inhibitor (TKI) therapy is an important treatment option for advanced renal cell carcinoma (RCC). Many RCC patients may fail to respond or be resistant to TKI therapy. We aimed to explore the key mechanisms of neoadjuvant therapy résistance. We obtained tumor samples from matched pre-treatment biopsy and post-treatment surgical samples and performed single-cell RNA sequencing. Sunitinib-resistant ccRCC cell lines were established. Ferroptosis was detected by ferrous ion and lipid peroxidation levels. Tumor growth and resistance to Sunitinib was validated in vitro and vivo. Immunohistochemistry was used to validate the levels key genes and lipid peroxidation. Multi-center cohorts were included, including TCGA, ICGC, Checkmate-025 and IMmotion151 clinical trial. Survival analysis was performed to identify the associated clinical and genomic variables. Intratumoral heterogeneity was first described in the whole neoadjuvant management. The signature of endothelial cells was correlated with drug sensitivity and progression-free survival. Ferroptosis was shown to be the key biological program in malignant cell resistance. We observed tissue lipid peroxidation was negatively correlated with IL6 and tumor response. TKI-resistant cell line was established. SLC7A11 knockdown promoted cell growth and lipid peroxidation, increased the ferroptosis level, and suppressed the growth of tumor xenografts significantly (P < 0.01). IL6 could reverse the ferroptosis and malignant behavior caused by SLC7A11 (-) via JAK2/STAT3 pathway, which was rescued by the ferroptosis inducer Erastin. Our data indicate that ferroptosis is a novel strategy for advanced RCC treatment, which activated by IL6, providing a new idea for resistance to TKIs.
Asunto(s)
Sistema de Transporte de Aminoácidos y+ , Carcinoma de Células Renales , Resistencia a Antineoplásicos , Ferroptosis , Neoplasias Renales , Terapia Neoadyuvante , Sunitinib , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Humanos , Neoplasias Renales/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Terapia Neoadyuvante/métodos , Sunitinib/farmacología , Animales , Línea Celular Tumoral , Ratones , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Proteínas Quinasas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Femenino , Masculino , Terapia Molecular Dirigida , Interleucina-6/metabolismo , Interleucina-6/genética , Progresión de la EnfermedadRESUMEN
BACKGROUND: Malignant mesothelioma is a type of infrequent tumor that is substantially related to asbestos exposure and has a terrible prognosis. We tried to produce a fibroblast differentiation-related gene set for creating a novel classification and prognostic prediction model of MESO. METHOD: Three databases, including NCBI-GEO, TCGA, and MET-500, separately provide single-cell RNA sequencing data, bulk RNA sequencing profiles of MESO, and RNA sequencing information on bone metastatic tumors. Dimensionality reduction and clustering analysis were leveraged to acquire fibroblast subtypes in the MESO microenvironment. The fibroblast differentiation-related genes (FDGs), which were associated with survival and subsequently utilized to generate the MESO categorization and prognostic prediction model, were selected in combination with pseudotime analysis and survival information from the TCGA database. Then, regulatory network was constructed for each MESO subtype, and candidate inhibitors were predicted. Clinical specimens were collected for further validation. RESULT: A total of six fibroblast subtypes, three differentiation states, and 39 FDGs were identified. Based on the expression level of FDGs, three MESO subtypes were distinguished in the fibroblast differentiation-based classification (FDBC). In the multivariate prognostic prediction model, the risk score that was dependent on the expression level of several important FDGs, was verified to be an independently effective prognostic factor and worked well in internal cohorts. Finally, we predicted 24 potential drugs for the treatment of MESO. Moreover, immunohistochemical staining and statistical analysis provided further validation. CONCLUSION: Fibroblast differentiation-related genes (FDGs), especially those in low-differentiation states, might participate in the proliferation and invasion of MESO. Hopefully, the raised clinical subtyping of MESO would provide references for clinical practitioners.
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The reliability and safety of diesel engines gradually decrease with the increase in running time, leading to frequent failures. To address the problem that it is difficult for the traditional fault status identification methods to identify diesel engine faults accurately, a diesel engine fault status identification method based on synchro squeezing S-transform (SSST) and vision transformer (ViT) is proposed. This method can effectively combine the advantages of the SSST method in processing non-linear and non-smooth signals with the powerful image classification capability of ViT. The vibration signals reflecting the diesel engine status are collected by sensors. To solve the problems of low time-frequency resolution and weak energy aggregation in traditional signal time-frequency analysis methods, the SSST method is used to convert the vibration signals into two-dimensional time-frequency maps; the ViT model is used to extract time-frequency image features for training to achieve diesel engine status assessment. Pre-set fault experiments are carried out using the diesel engine condition monitoring experimental bench, and the proposed method is compared with three traditional methods, namely, ST-ViT, SSST-2DCNN and FFT spectrum-1DCNN. The experimental results show that the overall fault status identification accuracy in the public dataset and the actual laboratory data reaches 98.31% and 95.67%, respectively, providing a new idea for diesel engine fault status identification.
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Background: Primary squamous cell carcinoma of the thyroid (PSCCT) is a rare malignant tumor. The incidence rate of PSCCT is less than 1%. However, the diagnosis and treatment of PSCCT are limited. Surgical resection is considered to be one of the few effective intervention methods. In this article, we reported a case of taking tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) for PSCCT. Case summary: An 80-year-old male was admitted to our hospital with dyspnea, cough, wheezing, and hoarseness for a giant thyroid mass. He underwent bronchoscopy and tracheal stent implantation to alleviate the respiratory obstruction. Then he accepted right partial thyroid and right lymph node biopsy. Postoperative pathology revealed squamous cell carcinoma. Subsequently, he underwent an endoscopy to exclude upper gastrointestinal squamous cell carcinoma. Finally, he was diagnosed with PSCCT. The patient was tentatively treated with a combination of Anlotinib and Sintilimab. After two courses, the tumor volume significantly reduced in MRI images and shrank further after five courses of combined treatment. Unfortunately, the patient died of fulminant liver failure and autoimmune liver disease after 5-month-treatment. Conclusion: TKIs combined with ICIs may be an effective and novel way for PSCCT treatment, but immune-related complications, especially liver damage, should be cared.
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Osteoarthritis (OA) is a highly prevalent whole-joint disease that causes disability and pain and affects a patient's quality of life. However, currently, there is a lack of effective early diagnosis and treatment. Although stem cells can promote cartilage repair and treat OA, problems such as immune rejection and tumorigenicity persist. Extracellular vesicles (EVs) can transmit genetic information from donor cells and mediate intercellular communication, which is considered a functional paracrine factor of stem cells. Increasing evidences suggest that EVs may play an essential and complex role in the pathogenesis, diagnosis, and treatment of OA. Here, we introduced the role of EVs in OA progression by influencing inflammation, metabolism, and aging. Next, we discussed EVs from the blood, synovial fluid, and joint-related cells for diagnosis. Moreover, we outlined the potential of modified and unmodified EVs and their combination with biomaterials for OA therapy. Finally, we discuss the deficiencies and put forward the prospects and challenges related to the application of EVs in the field of OA.
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A small-scale delivery medium for CO2 laser energy with stable performance, flexibility, and high-strength is crucial in extreme laser processing environments, especially for minimally invasive surgery in high-humidity, twisty and narrow channels. Here, flexible and robust multimaterial infrared fibers made of selenium-based chalcogenide glasses and thermoplastic polymer were developed with a low loss of 7.18 dB/m at 10.6 µm. The resulting fibers were capable of stably delivering single-mode CO2 laser with 0.42 W average power. Moreover, to achieve precise control over the fibers in the practical clinical environment, customized co-polymers of polyphenylene sulfone resin and polyvinylidene fluoride were used as the fiber built-in jackets. Consequently, the fibers exhibited hydrophobicity, thermostability, high tensile strength, and low bending stiffness. The results demonstrated that the fibers can be used to deliver CO2 laser energy for fabric cutting and bio-tissues ablation, making them attractive for CO2 laser material processing and minimally invasive laser surgery.
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Objective: To analyze the role of PD-1/PD-L1 signaling pathway in regulating T cell activation and secretion of proinflammatory factors in atrial fibrillation. Methods: Forty-five patients with atrial fibrillation admitted to the cardiology department of our hospital from July 2019 to March 2021 were selected to be included in the atrial fibrillation group, and another 45 healthy volunteers were selected as the control group to compare the changes of T cell CD69 and human leukocyte antigen-DR (HLA-DR) expression in the peripheral blood of the two study groups; compare the changes of programmed death factor-1 on CD4+ and CD8+ lymphocytes in the peripheral blood of the two groups (PD-1) expression changes and PD-L1 and PD-L2 expression changes on peripheral blood myeloid dendritic cells (mDCs) cells; compare the changes of interleukin-2, interleukin-6, interleukin-10, and interleukin-17A (IL-2, IL-6, IL-10, and IL-17), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) concentrations on peripheral blood inflammatory factors in the two groups; and isolate the two groups of peripheral blood mDCs cells; α interferon upregulated PD-L1 expression in the cells and analyzed the effect of PD-L1 expression on the ability of mDCs to stimulate T cells to secrete cytokines. Results: The positive expression rates of CD69 and HLA-DR on peripheral blood CD3+ T lymphocytes were significantly higher in patients in the atrial fibrillation group than in the control group, and the differences were statistically significant (P < 0.01). The positive expression rate of PD-1 on CD4+ lymphocytes was significantly lower in patients in the atrial fibrillation group than in the control group (P < 0.01). There was no statistically significant difference between the two groups in terms of PD-1 positive expression rate on CD8+ lymphocytes (P > 0.05). The positive expression rate of PD-L1 on mDCs cells was significantly lower in patients in the atrial fibrillation group than in the control group (P < 0.01), and there was no statistically significant difference between the two groups in the positive expression rate of PD-L2 on mDCs cells, PD-L1, and PD-L2 on CD4+ and CD8+ T cells (P > 0.05). The concentrations of IL-2, IL-6, IL-10, and IFN-γ in peripheral blood were significantly higher in patients in the atrial fibrillation group than in the control group (P < 0.05), and there was no statistically significant difference in the comparison of IL-17A and TNF concentrations in peripheral blood between the two groups (P > 0.05). In the atrial fibrillation group, the ability of mDCs to stimulate T cells to secrete IL-2 and IFN-γ was significantly higher, and the ability to secrete IL-10 was significantly lower compared with the control group (P < 0.05). After α interferon upregulated PD-L1 expression in cells, the ability of mDCs to stimulate T cells to secrete IL-2, IL-10, and IFN-γ cytokines was reversed in patients in the atrial fibrillation group, and the differences compared with the control group were not statistically significant (P > 0.05). Conclusion: PD-1/PD-L1 signaling pathway may play an immunomodulatory role in the pathogenesis of atrial fibrillation by promoting increased secretion of inflammatory factors through regulating T cell activation.