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Mitoribosomes are essential for the production of biological energy. The Human Mitoribosomal Small Subunit unit (MRPS) family, responsible for encoding mitochondrial ribosomal small subunits, is actively engaged in protein synthesis within the mitochondria. Intriguingly, MRPS family genes appear to play a role in cancer. A multistep process was employed to establish a risk model associated with MRPS genes, aiming to delineate the immune and pharmacogenomic landscapes in clear cell renal cell carcinoma (ccRCC). MRPScores were computed for individual patients to assess their responsiveness to various treatment modalities and their susceptibility to different therapeutic targets and drugs. While MRPS family genes have been implicated in various cancers as oncogenes, our findings reveal a contrasting tumor suppressor role for MRPS genes in ccRCC. Utilizing an MRPS-related risk model, we observed its excellent prognostic capability in predicting survival outcomes for ccRCC patients. Remarkably, the subgroup with high MRPS-related scores (MRPScore) displayed poorer prognosis but exhibited a more robust response to immunotherapy. Through in silico screening of 2183 drug targets and 1646 compounds, we identified two targets (RRM2 and OPRD1) and eight agents (AZ960, carmustine, lasalocid, SGI-1776, AZD8055_1059, BPD.00008900_1998, MK.8776_2046, and XAV939_1268) with potential therapeutic implications for high-MRPScore patients. Our study represents the pioneering effort in proposing that molecular classification, diagnosis, and treatment strategies can be formulated based on MRPScores. Indeed, a high MRPScore profile appears to elevate the risk of tumor progression and mortality, potentially through its influence on immune regulation. This suggests that the MRPS-related risk model holds promise as a prognostic predictor and may offer novel insights into personalized therapeutic strategies.
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Aberrant regulation of ubiquitination is an essential fundamental process in tumors, especially intrahepatic cholangiocarcinoma (iCCA). We reported that OTUB2, an OTU deubiquitinase, is upregulated in iCCA and stabilizes the CTNNB1-ZEB1 axis, resulting in epithelial-mesenchymal transition (EMT) and iCCA metastasis. Mechanistically, OTUB2 promotes CTNNB1 expression by interacting with the E3 ligase TRAF6. OTUB2 inhibits the lysosomal degradation of CTNNB1 by interacting with TRAF6 and thus regulates the progression of iCCA through ZEB1. Clinically, high OTUB2 expression is related to increased ZEB1 expression and activity and reduced overall survival in iCCA patients. Therefore, advanced iCCA patients may benefit from drugs targeting OTUB2 and its pathway.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Fator 6 Associado a Receptor de TNF/metabolismo , Colangiocarcinoma/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/metabolismo , Enzimas Desubiquitinantes/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Tioléster Hidrolases/metabolismoRESUMO
Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.
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Carbocianinas , Mitocôndrias , Recidiva Local de Neoplasia , Terapia Fototérmica , Neoplasias da Próstata , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Terapia Fototérmica/métodos , Humanos , Animais , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Linhagem Celular Tumoral , Carbocianinas/química , Imagem Óptica/métodos , Camundongos , Cirurgia Assistida por Computador/métodos , Corantes Fluorescentes/química , Camundongos Nus , Camundongos Endogâmicos BALB C , Raios Infravermelhos , Verde de Indocianina/química , Verde de Indocianina/uso terapêutico , Verde de Indocianina/farmacologiaRESUMO
Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease, which mainly damages patients' exocrine glands. Sensitive early diagnostic indicators and effective treatments for pSS are lacking. Using machine learning methods to find diagnostic markers and effective therapeutic ways for pSS is of great significance. In our study, first, 1643 differentially expressed genes (DEGs; 737 were upregulated and 906 were downregulated) were ultimately screened out and analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes based on the datasets from the Gene Expression Omnibus. Then, support vector machine, least absolute shrinkage and selection operator regression, random forest, and weighted correlation network analysis were used to screen out feature genes from DEGs. Subsequently, the intersection of the feature genes was taken to screen 10 genes as hub genes. Meanwhile, the analysis of the diagnostic efficiency of 10 hub genes showed their good diagnostic value for pSS, which was validated through immunohistochemistry on the paraffin sections of the labial gland. Subsequently, a multi-factor regulatory network and correlation analysis of hub genes were performed, and the results showed that ELAVL1 and IGF1R were positively correlated with each other but both negatively correlated with the other seven hub genes. Moreover, several meaningful results were detected through the immune infiltration landscape. Finally, we used molecular docking to screen potential therapeutic compounds of pSS based on the hub genes. We found that the small molecules DB08006, DB08036, and DB15308 had good docking scores with ELAVL1 and IGF1R simultaneously. Our study might provide effective diagnostic biomarkers and new therapeutic ideas for pSS.
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Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/genética , Simulação de Acoplamento Molecular , Lábio , Aprendizado de Máquina , ParafinaRESUMO
Nanomaterial-derived quantum dots (QDs) are excellent electrochemiluminescence (ECL) luminophores and play an important role in optical sensing due to their excellent water solubility, good biocompatibility and tunable molecular size. In this work, a novel strategy was designed to form nano-hybrid Ti3C2 QDs-AuNPs in situ as a luminophore based on the unique reducibility of Ti3C2 QDs, which showed remarkable and stable ECL performance. Here, AuNPs were formed in situ without the addition of reducing agents and stabilizers, leading to threefold enhancement of the ECL signal of Ti3C2 QDs due to their excellent charge transfer capability. Meanwhile, Ti3C2 QDs-AuNPs with abundant Ti atoms also acted as recognition units. Through skillful combination with hybridization chain reaction (HCR) to expose more phosphate, an ECL platform was constructed to detect polynucleotide kinase (PNK) with good specificity and sensitivity. A lower limit of detection limit of 2.7×10-5 U mL-1 was achieved, with a wide linear relationship ranging from 0.0001 to 10 U mL-1. This novel strategy provides a guide for the application of nano-hybrid Ti3C2 QDs-AuNPs as a luminophore in the field of ECL bioanalysis. Novel in situ-formed nano-hybrid Ti3C2 QDs-AuNPs were prepared as a luminophore, with threefold enhancement of the ECL signal of Ti3C2 QDs.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Pontos Quânticos , Técnicas Eletroquímicas , Ouro , Medições Luminescentes , TitânioRESUMO
Electrochemiluminescence (ECL) of luminol is a well-established methodology in analytical chemistry and bioimaging. Developing novel strategies to enhance the ECL signal of this model emitter is a challenging but rewarding task. In this work, we introduced the high-intensity focused ultrasound (HIFU), as a pretreatment means and a non-invasive way to trigger and boost the ECL signal with a 40-fold significant enhancement in the luminol-O2 system without the addition of exogenous co-reactants. The superoxide anion (O2-â¢) generated in situ by HIFU was the key initiator for boosting the ECL emission as demonstrated in this study for the first time. This promising co-reactant-free strategy could find potential applications for ultrasensitive ECL detection in the analysis of complex biological entities.
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Técnicas Biossensoriais , Luminol , Técnicas Eletroquímicas/métodos , Técnicas Biossensoriais/métodos , Medições Luminescentes/métodos , Limite de DetecçãoRESUMO
Stimulated Raman Scattering Microscopy (SRS) is a powerful tool for label-free detailed recognition and investigation of the cellular and subcellular structures of living cells. Determining subcellular protein localization from the cell level of SRS images is one of the basic goals of cell biology, which can not only provide useful clues for their functions and biological processes but also help to determine the priority and select the appropriate target for drug development. However, the bottleneck in predicting subcellular protein locations of SRS cell imaging lies in modeling complicated relationships concealed beneath the original cell imaging data owing to the spectral overlap information from different protein molecules. In this work, a multiple parallel fusion network, MPFnetwork, is proposed to study the subcellular locations from SRS images. This model used a multiple parallel fusion model to construct feature representations and combined multiple nonlinear decomposing algorithms as the automated subcellular detection method. Our experimental results showed that the MPFnetwork could achieve over 0.93 dice correlation between estimated and true fractions on SRS lung cancer cell datasets. In addition, we applied the MPFnetwork method to cell images for label-free prediction of several different subcellular components simultaneously, rather than using several fluorescent labels. These results open up a new method for the time-resolved study of subcellular components in different cells, especially cancer cells.
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Microscopia , Análise Espectral Raman , Microscopia/métodos , Microscopia Óptica não Linear/métodos , Transporte Proteico , Proteínas/metabolismo , Análise Espectral Raman/métodosRESUMO
Metabolic reprogramming endows cancer cells with the ability to adjust metabolic pathways to support heterogeneously biological processes. However, it is not known how the reprogrammed activities are implemented during differentiation of cancer stem cells (CSCs). In this study, we demonstrated that liver CSCs relied on the enhanced mitochondrial function to maintain stemness properties, which is different from aerobic glycolysis playing main roles in the differentiated non-CSCs. We found that liver CSCs exhibit increased mitochondrial respiratory capacity and that complex-I of mitochondria was necessary for stemness properties of liver CSCs through regulation of mitochondrial respiration. Bioinformatics analysis reveals that mitochondrial ribosomal protein S5 (MRPS5) is closely related with the function of complex-I. Further experiments confirmed that MRPS5 promoted the production of nicotinamide adenine dinucleotide (NAD+ ), which is necessary for enhanced mitochondrial function in liver CSCs. MRPS5 played a critical role for liver CSCs to maintain stemness properties and to participate in tumor progression. Mechanistically, the acetylation status of MRPS5 is directly regulated by NAD+ dependent deacetylase sirtuin-1 (SIRT1), which is abundant in liver CSCs and decreased during differentiation. Deacetylated MRPS5 locates in mitochondria to promote the function complex-I and the generation of NAD+ to enhance mitochondrial respiration. Conversely, the acetylated MRPS5 gathered in nuclei leads to increased expression of glycolytic proteins and promotion of the Warburg Effect. Therefore, liver CSCs transform mitochondrial-dependent energy supply to a Warburg phenotype by the dual function of MRPS5. Clinical analysis of SIRT1 and MRPS5 expression in tumor tissues showed the SIRT1High /Cytoplasmic-MRPS5High profile was associated with patients with hepatocellular carcinoma with poor prognosis. Conclusion: SIRT1/MRPS5 axis participates in metabolic reprogramming to facilitate tumor progression and may serve as a promising therapeutic target of liver cancer.
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Carcinoma Hepatocelular/genética , Reprogramação Celular/genética , Neoplasias Hepáticas/genética , Proteínas Mitocondriais/genética , NAD/metabolismo , Proteínas Ribossômicas/genética , Sirtuína 1/metabolismo , Acetilação/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/patologia , Diferenciação Celular/genética , Metilação de DNA/genética , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Sensibilidade e Especificidade , Células Tumorais CultivadasRESUMO
Several studies have investigated the relationship between ABCB1 G2677T/A polymorphism and breast cancer susceptibility; however, the published results remain controversial. Thus, we conducted a meta-analysis to synthetically evaluate the association of this polymorphism with breast cancer risk. A computerized literature search was systematically carried out in PubMed, EMBASE, ScienceDirect, China National Knowledge Infrastructure and Wanfang Databases to identify the published case-control studies investigating the relationship between ABCB1 G2677T/A polymorphism and breast cancer risk. The strength of association was assessed using odds ratios (ORs) with 95% confidence intervals (CIs). In total, six studies, including 4,791 cases and 7,042 controls, were included. The results of our quantitative synthesis suggest that there is no significant association between ABCB1 G2677T/A polymorphism and breast cancer risk in overall comparisons under four genetic models (heterozygote: OR = 1.01, 95% CI = 0.92-1.09, P = 0.90; homozygote: OR = 1.01, 95% CI = 0.65-1.55, P = 0.97; recessive model: OR = 1.06, 95% CI = 0.75-1.50, P = 0.76; and dominant model: OR = 0.98, 95% CI = 0.77-1.24, P = 0.85). Similarly, no significant association was observed in the stratification analyses by ethnicity and control source. In conclusion, this meta-analysis suggests that ABCB1 G2677T/A polymorphism is not associated with genetic susceptibility to breast cancer.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Povo Asiático/estatística & dados numéricos , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Prognóstico , Fatores de Risco , População Branca/estatística & dados numéricosRESUMO
T cells modified with anti-CD19 chimeric antigen receptor (CAR) containing either CD28 or 4-1BB (also termed TNFRSF9, CD137) costimulatory signalling have shown great potential in the treatment of acute lymphoblastic leukaemia (ALL). However, the difference between CD28 and 4-1BB costimulatory signalling in CAR-T treatment has not been well elucidated in clinical trials. In this study, we treated 10 relapsed or refractory ALL patients with the second generation CD19 CAR-T. The first 5 patients were treated with CD28-CAR and the other 5 patients were treated with 4-1BB CAR-T. All the 10 patients were response-evaluable. Three patients achieved complete remission and 1 patient with extramedullary disease achieved partial response after CD28-CAR-T treatment. In the 4-1BB CAR-T treatment group, 3 patients achieved complete remission. Furthermore, FLT-3 ligand (FLT3LG) was highly correlated with response time and may serve as a prognosis factor. No severe adverse events were observed in these 10 treated patients. Our study showed that both CD28 CAR-T and 4-1BB CAR-T both worked for response but they differed in response pattern (peak reaction time, reaction lasting time and reaction degree), adverse events, cytokine secretion and immune-suppressive factor level.
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Antígenos CD19/imunologia , Antígenos CD28/imunologia , Imunoterapia Adotiva , Proteínas de Neoplasias/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
Chimeric antigen receptor T (CAR-T) cells have shown promising efficacy in treatment of hematological malignancies, but its applications in solid tumors need further exploration. In this study, we investigated CAR-T therapy targeting carcino-embryonic antigen (CEA)-positive colorectal cancer (CRC) patients with metastases to evaluate its safety and efficacy. Five escalating dose levels (DLs) (1 × 105 to 1 × 108/CAR+/kg cells) of CAR-T were applied in 10 CRC patients. Our data showed that severe adverse events related to CAR-T therapy were not observed. Of the 10 patients, 7 patients who experienced progressive disease (PD) in previous treatments had stable disease after CAR-T therapy. Two patients remained with stable disease for more than 30 weeks, and two patients showed tumor shrinkage by positron emission tomography (PET)/computed tomography (CT) and MRI analysis, respectively. Decline of serum CEA level was apparent in most patients even in long-term observation. Furthermore, we observed persistence of CAR-T cells in peripheral blood of patients receiving high doses of CAR-T therapy. Importantly, we observed CAR-T cell proliferation especially in patients after a second CAR-T therapy. Taken together, we demonstrated that CEA CAR-T cell therapy was well tolerated in CEA+ CRC patients even in high doses, and some efficacy was observed in most of the treated patients.
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Adenocarcinoma/terapia , Antígeno Carcinoembrionário/genética , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/terapia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/imunologia , Adenocarcinoma/secundário , Idoso , Antígeno Carcinoembrionário/imunologia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Citotoxicidade Imunológica , Relação Dose-Resposta Imunológica , Feminino , Expressão Gênica , Humanos , Imunoterapia Adotiva , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Ativação Linfocitária , Depleção Linfocítica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/imunologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Engenharia de Proteínas , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/citologia , Linfócitos T/transplanteRESUMO
Despite the significant advancements in cancer treatment brought by immune checkpoint inhibitors (ICIs), their effectiveness in treating glioblastoma (GBM) remains highly dissatisfactory. Immunotherapy relies on the fundamental concept of T cell-mediated tumor killing (TTK). Nevertheless, additional investigation is required to explore its potential in prognostic prediction and regulation of tumor microenvironment (TME) in GBM. TTK sensitivity related genes (referred to as GSTTKs) were obtained from the TISIDB. The training cohort was available from the TCGA-GBM, while the independent validation group was gathered from GEO database. Firstly, we examined differentially expressed GSTTKs (DEGs) with limma package. Afterwards, the prognostic DEGs were identified and the TTK signature was established with univariate and LASSO Cox analyses. Next, we examined the correlation between the TTK signature and outcome of GBM as well as immune phenotypes of TME. Furthermore, the evaluation of TTK signature in predicting the effectiveness of immunotherapy has also been conducted. We successfully developed a TTK signature with an independent predictive value. Patients who had a high score experienced a worse prognosis compared to patients with low scores. The TTK signature showed a strong positive association with the infiltration degree of immunocyte and the presence of various immune checkpoints. Moreover, individuals with a lower score exhibited increased responsiveness to ICIs and experienced improved prognosis. In conclusions, we successfully developed and verified a TTK signature that has the ability to predict the outcome and immune characteristics of GBM. Furthermore, the TTK signature has the potential to direct the personalized immunotherapy for GBM.
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Au nano-clusters (Au NCs) were promising electrochemiluminescence (ECL) nano-materials. However, the small size of Au NCs presented a challenge in terms of their immobilization during the construction of an ECL biosensing platform. This limitation significantly hindered the wider application of Au NCs in the ECL field. In this work, we successfully used the reducibility of Ti3C2 to fabricate in situ a self-enhanced nano-probe Ti3C2-TiO2-Au NCs. The strategy of in situ generation not only improved the immobilization of Au NCs on the probe but also eliminated the requirement of adding reducing agents during preparation. In addition, in situ generated TiO2 could serve as a co-reaction accelerator, shortening the electron transfer distance between S2O82- and Au NCs, thereby improving the utilization of intermediates and enhancing the ECL response of Au NCs. The constructed ECL sensing platform could achieve sensitive detection of polynucleotide kinase (PNK). At the same time, the 5'-end phosphate group of DNA phosphorylation could chelate with a large amount of Ti on the surface of Ti3C2, thereby achieving the goal of specific detection of PNK. The sensor based on self-enhanced ECL probes had a broad dynamic range spanning for PNK detection from 10.0 to 1.0 × 107 µU mL-1, with a limit of detection of 1.6 µU mL-1. Moreover, the ECL sensor showed satisfactory detection performance in HeLa cell lysate and serum. This study not only provided insights for addressing the issue of ECL luminescence efficiency in Au NCs but also presented novel concepts for ECL self-enhancement strategies.
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Técnicas Biossensoriais , Ouro , Limite de Detecção , Medições Luminescentes , Polinucleotídeo 5'-Hidroxiquinase , Titânio , Titânio/química , Técnicas Biossensoriais/métodos , Humanos , Medições Luminescentes/métodos , Ouro/química , Polinucleotídeo 5'-Hidroxiquinase/análise , Técnicas Eletroquímicas/métodos , Nanopartículas Metálicas/química , Substâncias Luminescentes/químicaRESUMO
INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system and accounts for more than 90 % of all renal tumors. Resistance to targeted therapy has emerged as a pivotal factor that contributes to the progressive deterioration of patients with advanced RCC. Metabolic reprogramming is a hallmark of tumorigenesis and progression, with an increasing body of evidence indicating that abnormal lipid metabolism plays a crucial role in the advancement of renal clear cell carcinoma. OBJECTIVES: Clarify the precise mechanisms underlying abnormal lipid metabolism and drug resistance. METHODS: Bioinformatics screening and analyses were performed to identify hub gene. qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform biological functional experiments. RESULTS: In this study, we identified Mesoderm induction early response 2 (MIER2) as a novel biomarker for RCC, demonstrating its role in promoting malignancy and sunitinib resistance by influencing lipid metabolism in RCC. Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. Furthermore, Trichostatin A (TSA), an inhibitor of HDAC1, was found to impede the MIER2/HDAC1/P53/PGC1A pathway, offering potential benefits for patients with sunitinib-resistant renal cell cancer. CONCLUSION: Our findings highlight MIER2 as a key player in anchoring HDAC1 and inhibiting PGC1A expression through the deacetylation of P53, thereby inducing lipid accumulation in RCC and promoting drug resistance. Lipid-rich RCC cells compensate for energy production and sustain their own growth in a glycolysis-independent manner, evading the cytotoxic effects of targeted drugs and ultimately culminating in the development of drug resistance.
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The tumor microenvironment (TME) comprises immune-infiltrating cells that are closely linked to tumor development. By screening and analyzing genes associated with tumor-infiltrating M0 cells, we developed a risk model to provide therapeutic and prognostic guidance in clear cell renal cell carcinoma (ccRCC). First, the infiltration abundance of each immune cell type and its correlation with patient prognosis were analyzed. After assessing the potential link between the depth of immune cell infiltration and prognosis, we screened the infiltrating M0 cells to establish a risk model centered on three key genes (TMEN174, LRRC19, and SAA1). The correlation analysis indicated a positive correlation between the risk score and various stages of the tumor immune cycle, including B-cell recruitment. Furthermore, the risk score was positively correlated with CD8 expression and several popular immune checkpoints (ICs) (TIGIT, CTLA4, CD274, LAG3, and PDCD1). Additionally, the high-risk group (HRG) had higher scores for tumor immune dysfunction and exclusion (TIDE) and exclusion than the low-risk group (LRG). Importantly, the risk score was negatively correlated with the immunotherapy-related pathway enrichment scores, and the LRG showed a greater therapeutic benefit than the HRG. Differences in sensitivity to targeted drugs between the HRG and LRG were analyzed. For commonly used targeted drugs in RCC, including axitinib, pazopanib, temsirolimus, and sunitinib, LRG had lower IC50 values, indicating increased sensitivity. Finally, immunohistochemistry results of 66 paraffin-embedded specimens indicated that SAA1 was strongly expressed in the tumor samples and was associated with tumor metastasis, stage, and grade. SAA1 was found to have a significant pro-tumorigenic effect by experimental validation. In summary, these data confirmed that tumor-infiltrating M0 cells play a key role in the prognosis and treatment of patients with ccRCC. This discovery offers new insights and directions for the prognostic prediction and treatment of ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Microambiente Tumoral , Humanos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Prognóstico , Microambiente Tumoral/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Feminino , Masculino , Medição de Risco/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Imunoterapia/métodos , Sulfonamidas/uso terapêuticoRESUMO
Prostate cancer (PCa) is a leading cause of cancer-related death in men, and most PCa patients treated with androgen deprivation therapy will progress to metastatic castration-resistant prostate cancer (mCRPC) due to the lack of efficient treatment. Recently, lots of research indicated that photothermal therapy (PTT) was a promising alternative that provided an accurate and efficient prostate cancer therapy. A photothermic agent (PTA) is a basic component of PPT and is divided into organic and inorganic PTAs. Besides, the combination of PTT and other therapies, such as photodynamic therapy (PDT), immunotherapy (IT), chemotherapy (CT), etc., provides an more efficient strategy for PCa therapy. Here, we introduce basic information about PTT and summarize the PTT treatment strategies for prostate cancer. Based on recent works, we think the combination of PPT and other therapies provides a novel possibility for PCa, especially CRPC clinical treatment.
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Terapia Fototérmica , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Animais , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Imunoterapia , Fototerapia/métodosRESUMO
Cardiovascular health (CVH) score is not only associated with cardiovascular diseases, but also some disorders in other systems. This study aims to investigate the association between CVH score and the risk of fragility fractures. The analysis enrolled 89,464 participants at baseline in Kailuan study initiated in 2006-2007. All participants were then followed up every 2 years and the incidence of fragility fractures was recorded annually. A total CVH score was classified as low (0-49 points), moderate (50-79 points), and ideal (80-100 points). The primary outcome was incident fragility fractures before December 31, 2021. Kaplan-Meier was used to estimate cumulative incidence. Multivariable adjusted Cox proportional hazards regression models and time-dependent Cox hazards regression models were used to estimate fragility fracture hazard ratios (aHR) and 95% confidence intervals (95% CI). After 13.98 ± 2.84 years of follow-up, a total of 1534 cases of fragility fractures were identified, with an incidence density of 1.23 per 1000 person-years. Compared with the low CVH group, the risk of fragility fractures was significantly lower in moderate (aHR = 0.78, 95% CI: 0.66-0.92) and ideal CVH groups (aHR = 0.65, 95% CI: 0.51-0.83), particularly in the age <60 group (aHR = 0.72, 95% CI: 0.59-0.88; aHR= 0.55, 95% CI: 0.41-0.73, respectively). Time-dependent Cox hazards regression models, sensitivity analysis, and death competition model confirmed the reliability of these findings. The ideal CVH score is associated with a decreased risk of fragility fractures. With the increase of CVH score, the risk of fragility fracture decreases.
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Doenças Cardiovasculares , Humanos , Estudos de Coortes , Fatores de Risco , Reprodutibilidade dos Testes , Doenças Cardiovasculares/epidemiologia , Modelos de Riscos ProporcionaisRESUMO
Recent studies have highlighted the notable involvement of the crosstalk between hypoxia-inducible factor 2 alpha (HIF2α) and Wnt signaling components in tumorigenesis. However, the cellular function and precise regulatory mechanisms of HIF2α and Wnt signaling interactions in clear cell renal cell carcinoma (ccRCC) remain elusive. To analyze the correlation between HIF2α and Wnt signaling, we utilized the Cancer Genome Atlas - Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) public database, HIF2α RNA sequencing data, and conducted luciferase reporter assays. A Wnt-related gene set was employed to identify key regulators of Wnt signaling controlled by HIF2α in ccRCC. Furthermore, we assessed the biological effects of TCF7L2 on ccRCC metastasis and lipid metabolism in both in vivo and in vitro settings. Our outcomes confirm TCF7L2 as a key gene involved in HIF2α-mediated regulation of the canonical Wnt pathway. Functional studies demonstrate that TCF7L2 promotes metastasis in ccRCC. Mechanistic investigations reveal that HIF2α stabilizes TCF7L2 mRNA in a method based on m6A by transcriptionally regulating METTL3. Up-regulation of TCF7L2 enhances cellular fatty acid oxidation, which promotes histone acetylation. This facilitates the transcription of genes connected to epithelial-mesenchymal transition and ultimately enhances metastasis of ccRCC. These outcomes offer a novel understanding into the involvement of lipid metabolism in the signaling pathway regulation, offering valuable implications for targeted treatment in ccRCC.
RESUMO
Disulfidptosis, a newly discovered mode of cell death caused by excessive accumulation of intracellular disulfide compounds, is closely associated with tumor development. This study focused on the relationship between disulfidptosis and clear cell renal cell carcinoma (ccRCC). Firstly, the characterizations of disulfidptosis-related genes (DRGs) in ccRCC were showed, which included number variation (CNV), single nucleotide variation (SNV), DNA methylation, mRNA expression and gene mutation. Then, the ccRCC samples were classified into three clusters through unsupervised clustering based on DRGs. Survival and pathway enrichment differences were evaluated among the three clusters. Subsequently, the differentially expressed genes (DEGs) among the three clusters were screened by univariate Cox, LASSO, and multivariate Cox analysis, and five key DEGs were obtained. Based on the five key DEGs, the ccRCC samples were reclassified into two geneclusters and the survival differences and immune cell infiltration between two geneclusters was investigated. In next step, ccRCC samples were divided into two groups according to PCA scores of five key DEGs, namely high PCA score group (HPSG) and low PCA score group (LPSG). On this basis, differences in survival prognosis, immune cell infiltration and correlation with immune checkpoint, as well as differences in sensitivity to targeted drugs were compared between HPSG and LPSG. The expression levels of four immune checkpoints were higher in HPSG than in LPSG, whereas the LPSG was more sensitive to targeted drug therapy than the HPSG. Finally, validation experiments on HDAC4 indicated that HDAC4 could increase the proliferation and colony formation ability of ccRCC cells.
RESUMO
To investigate whether early-life exposure to the Great Famine of 1959-1961 in China was associated with the risk of digestive system cancer. The prospective cohort study involved 17 997 participants from the Kailuan Study (Tangshan, China) that began in 2006. All participants were divided into three groups based on their date of birth. The unexposed group (born from 1 October 1962 to 30 September 1964), fetal-exposed group (born from 1 October 1959 to 30 December 1961), and early-childhood-exposed group (born from 1 October 1956 to 30 December 1958). The Cox proportional hazards model was used to analyze the association between early famine exposure and digestive system cancer. During the mean follow-up period of (10.4 ± 2.2) years, a total of 223 digestive system cancer events occurred. Including 54 cases in the unexposed group (62.14/100 000 person-years), 57 cases in the fetal-exposed group (114.8/100 000 person-years), and 112 cases in the early-childhood-exposure group (122.2/100 000 person-years). After adjusting covariates, compared with the unexposed group, the HR and 95% CI were 1.85 (1.28, 2.69) for participants in the fetal-exposed group and 1.92 (1.38, 2.66) for participants in the early-childhood-exposed group. No interactions were observed in our study. After classifying digestive system cancers, the HR and 95% CI were 2.02 (1.03, 3.97) for colorectal cancer for participants in the fetal-exposed group and 2.55 (1.43, 4.55) for participants in the early-childhood-exposed group. The HR and 95% CI were (1.13, 3.83) of liver cancer for participants in the fetal-exposed group and 1.15 (0.63, 2.10) for participants in the early-childhood-exposed group. Early-life famine exposure was associated with a higher risk of digestive system cancer in adulthood. Fetal-exposed individuals might increase the risk of colorectal cancer and liver cancer, and early childhood-exposed might increase the risk of colorectal cancer.