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1.
Clin Lab ; 70(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38868885

RESUMO

BACKGROUND: Malignant pleural effusion (MPE) is a common complication of non-small cell lung cancer (NSCLC). Patients with NSCLC exhibit a high rate of epidermal growth factor receptor (EGFR) mutations. The detection of EGFR mutations is usually time-consuming and costly. This study aimed at identifying potential biomarkers of EGFR mutations in MPE of NSCLC patients by metabolomics. METHODS: In total, 58 MPE samples from 30 EGFR mutant and from 28 wild-type NSCLC patients were collected and analyzed by using hydrogen nuclear magnetic resonance (1H NMR) based metabolomics and UPLC-MS/MS based amino acid analysis. RESULTS: Our 1H NMR study showed a significant increase in the lysine levels but a significant decrease in the alanine levels in MPE of NSCLC patients with EGFR-mutant. Twelve amino acids in MPE were further determined by UPLC-MS/MS. It showed that alanine in MPE (6.34 ± 1.88 vs. 8.73 ± 3.68) were significantly decreased and leucine (3.13 ± 0.57 vs. 2.22 ± 0.13), lysine (2.19 ± 0.50 vs. 1.53 ± 0.40), and tyrosine (2.69 ± 0.71 vs. 1.89 ± 0.46) were increased in the EGFR mutation group; leucine (2.19 ± 0.50 vs. 1.53 ± 0.40), methionine (2.19 ± 0.50 vs. 1.53 ± 0.40), and threonine (2.19 ± 0.50 vs. 1.53 ± 0.40) in MPE were significantly lower in the EGRF 19 mutation compared with 21 mutation patients. The area under the receiver operating characteristic curve of 0.851 and 0.931 would be achieved by the logistic model for classification of EGFR-mutant patients from the wild-type controls or the exon 19 from exon 21 mutant patients. CONCLUSIONS: Amino acids in MPE are significantly altered and helpful in the diagnosis of EGFR-mutant patients from the wild-type controls or the exon 19 from exon 21 mutant patients with high accuracy, which is worthy of further study.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Metabolômica , Mutação , Humanos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Espectrometria de Massas em Tandem/métodos , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/diagnóstico , Adulto
2.
J Cell Mol Med ; 28(11): e18410, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38853457

RESUMO

Troponin T1 (TNNT1) plays a crucial role in muscle contraction but its role in cancer, particularly in kidney renal clear cell carcinoma (KIRC), is not well-understood. This study explores the expression, clinical significance and biological functions of TNNT1 in various cancers, with an emphasis on its involvement in KIRC. We analysed TNNT1 expression in cancers using databases like TCGA and GTEx, assessing its prognostic value, mutation patterns, methylation status and functional implications. The study also examined TNNT1's effect on the tumour microenvironment and drug sensitivity in KIRC, complemented by in vitro TNNT1 knockdown experiments in KIRC cells. TNNT1 is overexpressed in several cancers and linked to adverse outcomes, showing frequent upregulation mutations and abnormal methylation. Functionally, TNNT1 connects to muscle and cancer pathways, affects immune infiltration and drug responses, and its overexpression in KIRC is associated with advanced disease and reduced survival. Knocking down TNNT1 curbed KIRC cell growth. TNNT1's aberrant expression plays a significant role in tumorigenesis and immune modulation, highlighting its value as a prognostic biomarker and a potential therapeutic target in KIRC and other cancers. Further studies are essential to understand TNNT1's oncogenic mechanisms in KIRC.


Assuntos
Carcinogênese , Carcinoma de Células Renais , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais , Troponina T , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Imunomodulação/genética , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Mutação/genética , Prognóstico , Troponina T/metabolismo , Troponina T/genética , Microambiente Tumoral/imunologia
3.
Exp Mol Pathol ; 137: 104911, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38861838

RESUMO

BACKGROUND: Recently, consensus molecular subtypes (CMSs) have been proposed as a robust transcriptome-based classification system for colorectal cancer (CRC). Tetraspanins (TSPANs) are transmembrane proteins. They have been associated with the development of numerous malignancies, including CRC, through their role as "master organizers" for multi-molecular membrane complexes. No previous study has investigated the correlation between TSPANs and CMS classification. Herein, we investigated the expression of TSPANs in patient-derived primary CRC tissues and their CMS classifications. METHODS: RNA samples were derived from primary CRC tissues (n = 100 patients diagnosed with colorectal adenocarcinoma) and subjected to RNA sequencing for transcriptome-based CMS classification and TSPAN-relevant analyses. Immunohistochemistry (IHC) and immunofluorescence (IF) stains were conducted to observe the protein expression level. To evaluate the relative biological pathways, gene-set enrichment analysis was performed. RESULTS: Of the highly expressed TSPAN genes in CRC tissues (TSPAN8, TSPAN29, and TSPAN30), TSPAN8 was notably overexpressed in CMS3-classified primary tissues. The overexpression of TSPAN8 protein in CMS3 CRC was also observed by IHC and IF staining. As a result of gene-set enrichment analysis, TSPAN8 may potentially play a role in organizing signaling complexes for kinase-based metabolic deregulation in CMS3 CRC. CONCLUSIONS: The present study reports the overexpression of TSPAN8 in CMS3 CRC. This study proposes TSPAN8 as a subtype-specific biomarker for CMS3 CRC. This finding provides a foundation for future CMS-based studies of CRC, a complex disease and the second leading cause of cancer mortality worldwide.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Tetraspaninas , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/classificação , Tetraspaninas/genética , Tetraspaninas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/classificação , Transcriptoma/genética , Imuno-Histoquímica
4.
Nat Commun ; 15(1): 5069, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871730

RESUMO

Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.


Assuntos
Vesículas Extracelulares , Neoplasias da Próstata , Proteoma , Humanos , Neoplasias da Próstata/urina , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Masculino , Vesículas Extracelulares/metabolismo , Proteoma/metabolismo , Idoso , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/metabolismo , Proteômica/métodos , Pessoa de Meia-Idade , Próstata/metabolismo , Próstata/patologia , Linhagem Celular Tumoral
5.
Biochemistry (Mosc) ; 89(5): 839-852, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38880645

RESUMO

Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and the most abundant population of immune cells infiltrating a tumor. TAMs can largely determine direction of anti-tumor immune response by promoting it or, conversely, contribute to formation of an immunosuppressive TME that allows tumors to evade immune control. Through interactions with tumor cells or other cells in the microenvironment and, as a result of action of anti-cancer therapy, macrophages can enter senescence. In this review, we have attempted to summarize information available in the literature on the role of senescent macrophages in tumors. With the recent development of senolytic therapeutic strategies aimed at removing senescent cells from an organism, it seems important to discuss functions of the senescent macrophages and potential role of the senolytic drugs in reprogramming TAMs to enhance anti-tumor immune response and improve efficacy of cancer treatment.


Assuntos
Senescência Celular , Neoplasias , Microambiente Tumoral , Macrófagos Associados a Tumor , Microambiente Tumoral/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Macrófagos/imunologia , Macrófagos/metabolismo , Biomarcadores Tumorais/metabolismo
6.
Arkh Patol ; 86(3): 5-11, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38881000

RESUMO

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are a promising inexpensive prognostic and predictive biomarker in breast cancer. High levels of TILs are associated with improved survival and higher probability to achieve pathological complete response in triple-negative breast cancer (TNBC). OBJECTIVE: To assess the level of TILs in TNBC samples and analyze the association between the level of TILs and the main pathological parameters, to identify their impact on long-term results. MATERIAL AND METHODS: The study included information on 140 patients with I-III stage TNBC and estrogen receptors <10%. Tumor tissue samples at baseline biopsies were evaluated the histological type, HER2 expression, estrogen expression levels, Ki-67 and TILs. The pathological response was evaluated according to the ypTNM, Miller-Payne, and RCB classifications. RESULTS: The average level of TILs in biopsy specimens before NACT was 29.3±23.1%. Low levels of TILs (<10%) were defined in 21% of cases, intermediate levels (≥10% to ≤40%) in 55% of cases, and high levels (>40%) in 24% of cases. Using the two-tiered system, low TILs (≤40%) were defined in 76% and high TILs (>40%) in 24% of cases. The level of TILs was correlated with histological grade (R=0.187; p=0.027) and estrogen receptor expression level (R=0.211; p=0.012). There were no significant differences depending on the level of TILs and other pathological parameters. Three-year event-free survival (EFS) in patients with high TILs levels was 95% versus 65% in the low TILs group (p=0.037). CONCLUSION: Stromal TILs are an important prognostic biomarker in TNBC. Using a cutoff of 40%, high TILs are significantly associated with longer EFS.


Assuntos
Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Prognóstico , Receptores de Estrogênio/metabolismo , Biomarcadores Tumorais/metabolismo , Receptor ErbB-2/metabolismo , Intervalo Livre de Doença
7.
Exp Dermatol ; 33(6): e15119, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38881438

RESUMO

This manuscript presents a comprehensive investigation into the role of lactate metabolism-related genes as potential prognostic markers in skin cutaneous melanoma (SKCM). Bulk-transcriptome data from The Cancer Genome Atlas (TCGA) and GSE19234, GSE22153, and GSE65904 cohorts from GEO database were processed and harmonized to mitigate batch effects. Lactate metabolism scores were assigned to individual cells using the 'AUCell' package. Weighted Co-expression Network Analysis (WGCNA) was employed to identify gene modules correlated with lactate metabolism. Machine learning algorithms were applied to construct a prognostic model, and its performance was evaluated in multiple cohorts. Immune correlation, mutation analysis, and enrichment analysis were conducted to further characterize the prognostic model's biological implications. Finally, the function of key gene NDUFS7 was verified by cell experiments. Machine learning resulted in an optimal prognostic model, demonstrating significant prognostic value across various cohorts. In the different cohorts, the high-risk group showed a poor prognosis. Immune analysis indicated differences in immune cell infiltration and checkpoint gene expression between risk groups. Mutation analysis identified genes with high mutation loads in SKCM. Enrichment analysis unveiled enriched pathways and biological processes in high-risk SKCM patients. NDUFS7 was found to be a hub gene in the protein-protein interaction network. After the expression of NDUFS7 was reduced by siRNA knockdown, CCK-8, colony formation, transwell and wound healing tests showed that the activity, proliferation and migration of A375 and WM115 cell lines were significantly decreased. This study offers insights into the prognostic significance of lactate metabolism-related genes in SKCM.


Assuntos
Ácido Láctico , Aprendizado de Máquina , Melanoma , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Melanoma/genética , Melanoma/metabolismo , Prognóstico , Ácido Láctico/metabolismo , Análise de Célula Única , Mutação , Transcriptoma , Melanoma Maligno Cutâneo , Linhagem Celular Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética
8.
Clin Exp Med ; 24(1): 120, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847945

RESUMO

Long non-coding RNAs (lncRNAs) are fundamental agents that govern tumor growth and metastasis across a spectrum of cancer types. Linc01503 is a novel lncRNA situated on human chromosome 19, and it is intricately linked with the pathogenesis of multiple human cancers, underscoring its substantial role and significance in cancer development. It has been recognized as a pivotal contributor to inducing malignant behaviors in lung cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, liver cancer and pancreatic cancer, among others. The dysregulation of linc01503 has been shown to strongly associate with advanced clinicopathological factors and foretell an unfavorable prognosis, indicating its prospective clinical significance as a valuable biomarker and therapeutic target for individuals with cancer. The primary objective of the current work is to present the intricate molecular pathways governed by linc01503 and its profound clinical relevance in the context of carcinogenesis. We also focus on the future prospects of linc01503-based clinical application. This will help us to better understand the regulatory mechanism of carcinogenesis and provide new ideas for precision molecular medicine.


Assuntos
Neoplasias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Neoplasias/genética , Neoplasias/terapia , Neoplasias/patologia , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo
9.
BMC Cancer ; 24(1): 701, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849726

RESUMO

BACKGROUND: Ovarian cancer is the first cause of death from gynecological malignancies mainly due to development of chemoresistance. Despite the emergence of PARP inhibitors, which have revolutionized the therapeutic management of some of these ovarian cancers, the 5-year overall survival rate remains around 45%. Therefore, it is crucial to develop new therapeutic strategies, to identify predictive biomarkers and to predict the response to treatments. In this context, functional assays based on patient-derived tumor models could constitute helpful and relevant tools for identifying efficient therapies or to guide clinical decision making. METHOD: The OVAREX study is a single-center non-interventional study which aims at investigating the feasibility of establishing in vivo and ex vivo models and testing ex vivo models to predict clinical response of ovarian cancer patients. Patient-Derived Xenografts (PDX) will be established from tumor fragments engrafted subcutaneously into immunocompromised mice. Explants will be generated by slicing tumor tissues and Ascites-Derived Spheroids (ADS) will be isolated following filtration of ascites. Patient-derived tumor organoids (PDTO) will be established after dissociation of tumor tissues or ADS, cell embedding into extracellular matrix and culture in specific medium. Molecular and histological characterizations will be performed to compare tumor of origin and paired models. Response of ex vivo tumor-derived models to conventional chemotherapy and PARP inhibitors will be assessed and compared to results of companion diagnostic test and/or to the patient's response to evaluate their predictive value. DISCUSSION: This clinical study aims at generating PDX and ex vivo models (PDTO, ADS, and explants) from tumors or ascites of ovarian cancer patients who will undergo surgical procedure or paracentesis. We aim at demonstrating the predictive value of ex vivo models for their potential use in routine clinical practice as part of precision medicine, as well as establishing a collection of relevant ovarian cancer models that will be useful for the evaluation of future innovative therapies. TRIAL REGISTRATION: The clinical trial has been validated by local research ethic committee on January 25th 2019 and registered at ClinicalTrials.gov with the identifier NCT03831230 on January 28th 2019, last amendment v4 accepted on July 18, 2023.


Assuntos
Biomarcadores Tumorais , Neoplasias Ovarianas , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Feminino , Humanos , Camundongos , Biomarcadores Tumorais/metabolismo , Modelos Animais de Doenças , Organoides , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Terapias em Estudo/métodos
10.
BMC Biol ; 22(1): 133, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38853238

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy with a pressing need for improved therapeutic response and prognosis prediction. This study delves into a novel predictive model related to ferroptosis, a regulated cell death mechanism disrupting metabolic processes. RESULTS: Single-cell sequencing data analysis identified subpopulations of HCC cells exhibiting activated ferroptosis and distinct gene expression patterns compared to normal tissues. Utilizing the LASSO-Cox algorithm, we constructed a model with 10 single-cell biomarkers associated with ferroptosis, namely STMN1, S100A10, FABP5, CAPG, RGCC, ENO1, ANXA5, UTRN, CXCR3, and ITM2A. Comprehensive analyses using these biomarkers revealed variations in immune infiltration, tumor mutation burden, drug sensitivity, and biological functional profiles between risk groups. Specific associations were established between particular immune cell subtypes and certain gene expression patterns. Treatment response analyses indicated potential benefits from anti-tumor immune therapy for the low-risk group and chemotherapy advantages for the high-risk group. CONCLUSIONS: The integration of this single-cell level model with clinicopathological features enabled accurate overall survival prediction and effective risk stratification in HCC patients. Our findings illuminate the potential of ferroptosis-related genes in tailoring therapy and prognosis prediction for HCC, offering novel insights into the intricate interplay among ferroptosis, immune response, and HCC progression.


Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Ferroptose/genética , Ferroptose/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Análise de Célula Única , Medicina de Precisão/métodos
11.
PLoS One ; 19(6): e0305252, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38857246

RESUMO

Renal cell carcinoma (RCC), accounting for 90% of all kidney cancer, is categorized into clear cell RCC (ccRCC) and non-clear cell RCC (non-ccRCC) for treatment based on the current NCCN Guidelines. Thus, the classification will be associated with therapeutic implications. This study aims to identify novel biomarkers to differentiate ccRCC from non-ccRCC using bioinformatics and machine learning. The gene expression profiles of ccRCC and non-ccRCC subtypes (including papillary RCC (pRCC) and chromophobe RCC (chRCC)), were obtained from TCGA. Differential expression genes (DEGs) were identified, and specific DEGs for ccRCC and non-ccRCC were explored using a Venn diagram. Gene Ontology and pathway enrichment analysis were performed using DAVID. The top ten expressed genes in ccRCC were then selected for machine learning analysis. Feature selection was operated to identify a minimum highly effective gene set for constructing a predictive model. The expression of best-performing gene set was validated on tissue samples from RCC patients using immunohistochemistry techniques. Subsequently, machine learning models for diagnosing RCC were developed using H-scores. There were 910, 415, and 835 genes significantly specific for DEGs in ccRCC, pRCC, and chRCC, respectively. Specific DEGs in ccRCC enriched in PD-1 signaling, immune system, and cytokine signaling in the immune system, whereas TCA cycle and respiratory, signaling by insulin receptor, and metabolism were enriched in chRCC. Feature selection based on Decision Tree Classifier revealed that the model with two genes, including NDUFA4L2 and DAT, had an accuracy of 98.89%. Supervised classification models based on H-score of NDUFA4L2, and DAT revealed that Decision Tree models showed the best performance with 82% accuracy and 0.9 AUC. NDUFA4L2 expression was associated with lymphovascular invasion, pathologic stage and pT stage in ccRCC. Using integrated bioinformatics and machine learning analysis, NDUFA4L2 and DAT were identified as novel biomarkers to differential diagnosis ccRCC from non-ccRCC.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Biologia Computacional , Neoplasias Renais , Aprendizado de Máquina , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Renais/genética , Neoplasias Renais/diagnóstico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Masculino , Feminino , Diagnóstico Diferencial
12.
Eur J Med Res ; 29(1): 318, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858746

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a common type of malignant tumor where the prognosis is dismal. Circular RNA (CircRNA) is a novel RNA that regulates downstream gene transcription and translation to influence the progression of HCC. However, the regulatory relationship that exists between E3 ligases, which is a class of post-translational modifying proteins, and circRNA remains unclear. METHODS: Based on the E3 ubiquitin ligase in the competitive endogenous RNA (ceRNA) network, a circRNA-regulated E3 ubiquitin ligase signature (CRE3UL) was developed. A CRE3UL signature was created using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis and merged it with clinicopathologic characteristics to generate a nomogram for prognosis prediction. The pRRophetic algorithm was utilized and immunological checkpoints were analyzed to compare the responses of patients in the high-risk group (HRG) and low-risk group (LRG) to targeted therapy and immunotherapy. Finally, experimental research will further elucidate the relationship between E3 ubiquitin ligase signature and HCC. RESULTS: HRG patients were found to have a worse prognosis than LRG patients. Furthermore, significant variations in prognosis were observed among different subgroups based on various clinical characteristics. The CRE3UL signature was identified as being an independent prognostic indicator. The nomogram that combined clinical characteristics and the CRE3UL signature was found to accurately predict the prognosis of HCC patients and demonstrated greater clinical utility than the current TNM staging approach. According to anticancer medication sensitivity predictions, the tumors of HRG patients were more responsive to gefitinib and nilotinib. From immune-checkpoint markers analysis, immunotherapy was identified as being more probable to assist those in the HRG. CONCLUSIONS: We found a significant correlation between the CRE3UL signature and the tumor microenvironment, enabling precise prognosis prediction for HCC patients. Additionally, a nomogram was developed that performs well in predicting the overall survival (OS) of HCC patients. This provides valuable guidance for clinicians in devising specific personalized treatment strategies.


Assuntos
Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Nomogramas , RNA Circular , Ubiquitina-Proteína Ligases , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Prognóstico , RNA Circular/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Imunoterapia/métodos , Masculino , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica
13.
Sci Rep ; 14(1): 13556, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866930

RESUMO

Abnormalities in the extracellular matrix (ECM) play important roles in the regulation and progression of clear cell renal cell carcinoma (ccRCC). The cysteine cathepsin is one of the major proteases involved in ECM remodeling and has been shown to be aberrantly expressed in multiple cancer types. However, the clinical significance and biological function of distinct cysteine cathepsins in ccRCC remain poorly understood. In this study, several bioinformatics databases, including UALCAN, TIMER, GEPIA and the Human Protein Atlas datasets, were used to analyze the expression and prognostic value of different cysteine cathepsin family members in ccRCC. We found that the expression level of CTSF was downregulated in tumor tissues and closely related to the poor survival of ccRCC patients. Further in vitro experiments suggested that CTSF overexpression suppressed the proliferation and migration of ccRCC cells. Moreover, the expression of CTSF was shown to be associated with several immune-infiltrating cells and immunomodulators in ccRCC. These results indicated that CTSF might be a promising diagnostic and prognostic marker in ccRCC.


Assuntos
Carcinoma de Células Renais , Catepsina F , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Prognóstico , Neoplasias Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Feminino , Masculino , Catepsina F/metabolismo , Catepsina F/genética , Linhagem Celular Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Movimento Celular/genética , Pessoa de Meia-Idade , Regulação para Baixo
14.
Breast Cancer Res ; 26(1): 100, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867307

RESUMO

BACKGROUND: Immunohistochemistry (IHC) and in situ hybridization (ISH) remain standard biomarkers for therapeutic decisions in human epidermal growth factor 2 (HER2)-positive breast cancers (BCs); however, they are insufficient to explain the heterogeneous anti-HER2 response. METHODS: We aimed to investigate the correlation of in situ HER2 RNA expression (isHRE), using RNAscope, with HER2 biomarkers and the impact of isHRE on the pathological complete response (pCR) rates of 278 patients with HER2 IHC/fluorescence ISH (FISH)-positive BC receiving neoadjuvant chemotherapy and anti-HER2 targeted treatment (NCTT). RESULTS: We validated HER2 RNAscope scoring as a semiquantitative method to determine isHRE and showed a positive correlation between RNAscope scores and pCR rates, with particularly different rates between patients with a score of 5 versus 1-4 BCs (66.7% vs. 15.9%, p < 0.0001). There were higher RNAscope scores and pCR rates in patients with HER2 IHC 3 + versus IHC 2+/FISH + BCs and HER2 RNAscope scores and pCR rates showed similar non-linear positive correlations with HER2 copy numbers and HER2/centromere 17 ratios. Moreover, in each HER2-positive IHC/FISH category, higher pCR rates were observed in patients with RNAscope scores of 5 versus 1-4 BC. Patients achieving pCR had BCs with notably higher HER2 RNAscope scores. Multivariate analysis identified HER2 RNAscope 5 as a strong pCR predictor [odds ratio = 10.865, p < 0.001]. The combined impact of multivariate analysis-defined pCR predictors demonstrated that a higher pCR rate was observed in patients with a score of 5 versus a score of 1-4 BCs regardless of the status of hormone receptor and mono-or dual anti-HER2 blockade. CONCUSIONS: Our results demonstrated that high isHRE (RNAscope score 5) is a strong pCR predictor in patients with HER2-positive BCs receiving NCTT, highlighting the complementary role of isHRE in stratifying HER2 status in tissue. Such stratification is relevant to anti-HER2 therapeutic efficacy, particularly using the cutoff of score 1-4 versus 5.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Hibridização in Situ Fluorescente , Terapia Neoadjuvante , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Adulto , Biomarcadores Tumorais/metabolismo , Idoso , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia de Alvo Molecular , Imuno-Histoquímica , Prognóstico , Trastuzumab/uso terapêutico , Resposta Patológica Completa
15.
PLoS One ; 19(6): e0299345, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38870176

RESUMO

INTRODUCTION: Cervical cancer presents a significant global health challenge, disproportionately impacting underserved populations with limited access to healthcare. Early detection and effective management are vital in addressing this public health concern. This study focuses on Glyoxalase-1 (GLO1), an enzyme crucial for methylglyoxal detoxification, in the context of cervical cancer. METHODS: We assessed GLO1 expression in cervical cancer patient samples using immunohistochemistry. In vitro experiments using HeLa cells were conducted to evaluate the impact of GLO1 inhibition on cell viability and migration. Single-cell RNA sequencing (scRNA-seq) and gene set variation analysis were utilized to investigate the role of GLO1 in the metabolism of cervical cancer. Additionally, public microarray data were analyzed to determine GLO1 expression across various stages of cervical cancer. RESULTS: Our analysis included 58 cervical cancer patients, and showed that GLO1 is significantly upregulated in cervical cancer tissues compared to normal cervical tissues, independent of pathological findings and disease stage. In vitro experiments indicated that GLO1 inhibition by S-p-bromobenzylglutathione cyclopentyl diester decreased cell viability and migration in cervical cancer cell lines. Analyses of scRNA-seq data and public gene expression datasets corroborated the overexpression of GLO1 and its involvement in cancer metabolism, particularly glycolysis. An examination of expression data from precancerous lesions revealed a progressive increase in GLO1 expression from normal tissue to invasive cervical cancer. CONCLUSIONS: This study highlights the critical role of GLO1 in the progression of cervical cancer, presenting it as a potential biomarker and therapeutic target. These findings contribute valuable insights towards personalized treatment approaches and augment the ongoing efforts to combat cervical cancer. Further research is necessary to comprehensively explore GLO1's potential in clinical applications.


Assuntos
Biomarcadores Tumorais , Lactoilglutationa Liase , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Feminino , Lactoilglutationa Liase/metabolismo , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Células HeLa , Progressão da Doença , Movimento Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pessoa de Meia-Idade , Sobrevivência Celular/efeitos dos fármacos , Adulto , Linhagem Celular Tumoral
16.
Pathol Oncol Res ; 30: 1611734, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38873175

RESUMO

Background: Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare forms of gastric tumors that encompass oxyntic gland adenoma (OGA), gastric adenocarcinoma of the fundic-gland type (GA-FG), and gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM). There is no consensus on the cause, classification, and clinicopathological features of GEN-FGMLs, and misdiagnosis is common because of similarities in symptoms. Methods: 37 cases diagnosed with GEN-FGMLs were included in this study. H&E-stained slides were reviewed and clinicopathological parameters were recorded. Immunohistochemical staining was conducted for MUC2, MUC5AC, MUC6, CD10, CD56, synaptophysin, chromograninA, p53, Ki67, pepsinogen-I, H+/K+-ATPase and Desmin. Results: The patients' ages ranged from 42 to 79 years, with a median age of 60. 17 were male and 20 were female. Morphologically, 19 OGAs, 16 GA-FGs, and two GA-FGMs were identified. Histopathological similarities exist between OGA, GA-FG, and GA-FGM. The tumors demonstrated well-formed glands, expanding with dense growth patterns comprising pale, blue-grey columnar cells with mild nuclear atypia. These cells resembled fundic gland cells. None of the OGA invaded the submucosal layer. The normal gastric pit epithelium covered the entire surface of the OGA and GA-FG, but the dysplasia pit epithelium covered the GA-FGM. Non-atrophic gastritis was observed in more than half of the background mucosa. All cases were diffusely positive for MUC6 and pepsinogen-I on immunohistochemistry. H+/K+-ATPase staining was negative or showed a scattered pattern in most cases. MUC5AC was expressed on the surface of GA-FGMs. p53 was focally expressed and the Ki67 index was low (1%-20%). Compared with OGA, GA-FG and GA-FGM were more prominent in the macroscopic view (p < 0.05) and had larger sizes (p < 0.0001). Additionally, GA-FG and GA-FGM exhibited higher Ki67 indices than OGA (p < 0.0001). Specimens with Ki-67 proliferation indices >2.5% and size >4.5 mm are more likely to be diagnosed with GA-FG and GA-FGM than OGA. Conclusion: GEN-FGMLs are group of well-differentiated gastric tumors with favourable biological behaviours, low cellular atypia, and low proliferation. Immunohistochemistry is critical for confirming diagnosis. Compared with OGA, GA-FG and GA-FGM have larger sizes and higher Ki67 proliferation indices, indicating that they play a critical role in the identification of GEN-FGML. Pathologists and endoscopists should be cautious to prevent misdiagnosis and overtreatment, especially in biopsy specimens.


Assuntos
Biomarcadores Tumorais , Mucosa Gástrica , Antígeno Ki-67 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Antígeno Ki-67/metabolismo , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Fundo Gástrico/patologia , Fundo Gástrico/metabolismo , Adenoma/patologia , Adenoma/metabolismo , Prognóstico
17.
Commun Biol ; 7(1): 677, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38830977

RESUMO

We present a quantitative sandwich immunoassay for CD63 Extracellular Vesicles (EVs) and a constituent surface cargo, EGFR and its activity state, that provides a sensitive, selective, fluorophore-free and rapid alternative to current EV-based diagnostic methods. Our sensing design utilizes a charge-gating strategy, with a hydrophilic anion exchange membrane functionalized with capture antibodies and a charged silica nanoparticle reporter functionalized with detection antibodies. With sensitivity and robustness enhancement by the ion-depletion action of the membrane, this hydrophilic design with charged reporters minimizes interference from dispersed proteins, thus enabling direct plasma analysis without the need for EV isolation or sensor blocking. With a LOD of 30 EVs/µL and a high relative sensitivity of 0.01% for targeted proteomic subfractions, our assay enables accurate quantification of the EV marker, CD63, with colocalized EGFR by an operator/sample insensitive universal normalized calibration. We analysed untreated clinical samples of Glioblastoma to demonstrate this new platform. Notably, we target both total and "active" EGFR on EVs; with a monoclonal antibody mAb806 that recognizes a normally hidden epitope on overexpressed or mutant variant III EGFR. Analysis of samples yielded an area-under-the-curve (AUC) value of 0.99 and a low p-value of 0.000033, surpassing the performance of existing assays and markers.


Assuntos
Receptores ErbB , Vesículas Extracelulares , Glioblastoma , Tetraspanina 30 , Humanos , Glioblastoma/sangue , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Tetraspanina 30/metabolismo , Receptores ErbB/metabolismo , Vesículas Extracelulares/metabolismo , Imunoensaio/métodos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/diagnóstico
18.
BMC Cancer ; 24(1): 689, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844907

RESUMO

We examined the expression of programmed death-ligand 1 (PD-L1) in carcinoma of unknown primary (CUP) and its potential implications. Tissue microarrays were constructed for 72 CUP cases (histologic subtypes: 22 adenocarcinoma, 15 poorly differentiated carcinoma, 19 squamous cell carcinoma, and 14 undifferentiated carcinoma; clinical subtype: favorable type 17 [23.6%], unfavorable type 55 [76.4%]), with immunohistochemical staining performed for PD-L1 (22C3, SP142, SP263, and 28 - 8), CK7, and CK20 to determine the association between staining results and clinicopathological parameters. In CUP, the PD-L1 positivity rate was 5.6-48.6% (tumor cells [TC] or tumor proportion score [TPS]: 5.6-36.1%, immune cell score [IC]: 8.3-48.6%, combined positive score [CPS]: 16.7%) using different cutoff values for 22C3 (TPS ≥ 1%, CPS ≥ 10), SP142 (TC ≥ 50%, IC ≥ 10%), SP263, and 28 - 8 (TC and IC ≥ 1%). PD-L1 SP142 TC and PD-L1 SP263 IC showed the lowest (5.6%) and highest (48.6%) positivity rates, respectively. The PD-L1 positivity rate did not significantly differ based on the histologic subtype, clinical subtype, or CK7/CK20 across clones. Considering TC κ ≥ 1%, TC κ ≥ 50%, IC κ ≥ 1%, and IC κ ≥ 10%, the PD-L1 positivity rate was TC = 4.2-36.1% and IC = 9.7-48.6%; the overall agreement between antibodies ranged from 69.4 to 93.1%, showing fair or better agreement (κ ≥ 0.21). In CUP, PD-L1 positivity varied depending on antibodies and scoring systems, with no difference observed according to histologic or clinical subtypes.


Assuntos
Antígeno B7-H1 , Biomarcadores Tumorais , Neoplasias Primárias Desconhecidas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Primárias Desconhecidas/metabolismo , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Adulto , Imuno-Histoquímica , Análise Serial de Tecidos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia
19.
Int Immunopharmacol ; 136: 112367, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38823177

RESUMO

SLC25A19 is a mitochondrial thiamine pyrophosphate (TPP) carrier that mediates TPP entry into the mitochondria. SLC25A19 has been recognized to play a crucial role in many metabolic diseases, but its role in cancer has not been clearly reported. Based on clinical data from The Cancer Genome Atlas (TCGA), the following parameters were analyzed among HCC patients: SLC25A19 expression, enrichment analyses, immune infiltration, ferroptosis and prognosis analyses. In vitro, the SLC25A19 high expression was validated by qRT-PCR and Immunohistochemistry. Subsequently, a series of cell function experiments, including CCK8, EdU, clone formation, trans-well and scratch assays, were conducted to illustrate the effect of SLC25A19 on the growth and metastasis of cancer cells. Meanwhile, indicators related to ferroptosis were also detected. SCL25A19 is highly expressed in HCC and predicts a poor prognosis. Elevated SLC25A19 expression in HCC patients was markedly associated with T stage, pathological status (PS), tumor status (TS), histologic grade (HG), and AFP. Our results indicate that SLC25A19 has a generally good prognosis predictive and diagnostic ability. The results of gene enrichment analyses showed that SLC25A19 is significantly correlated with immune infiltration, fatty acid metabolism, and ferroptosis marker genes. In vitro experiments have confirmed that silencing SLC25A19 can significantly inhibit the proliferation and migration ability of cancer cells and induce ferroptosis in HCC. In conclusion, these findings indicate that SLC25A19 is novel prognostic biomarker related to immune invasion and ferroptosis in HCC, and it is an excellent candidate for therapeutic target against HCC.


Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Humanos , Ferroptose/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Feminino , Masculino , Pessoa de Meia-Idade , Movimento Celular , Proliferação de Células
20.
Sci Rep ; 14(1): 13474, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866822

RESUMO

Esophageal adenocarcinoma (EAC) is one of the deadliest tumor entities worldwide, with a 5-year survival rate of less than 25%. Unlike other tumor entities, personalized therapy options are rare, partly due to the lack of knowledge about specific subgroups. In this publication, we demonstrate a subgroup of patients with EAC in a large screening cohort of 826 patients, characterized by specific morphological and immunohistochemical features. This subgroup represents approximately 0.7% (6/826) of the total cohort. Morphological features of this subgroup show a striking clear cytoplasm of the tumour cells and the parallel existence of rare growth patterns like yolk sac-like differentiation and enteroblastic differentiation. Immunohistochemistry reveals expression of the fetal gut cell-like proteins Sal-like protein 4 (SALL4), claudin-6, and glypican 3. Interestingly, we find a correlation with alterations of SWI/SNF-complex associated genes, which are supposed to serve as tumor suppressor genes in various tumour entities. Our results suggest a possible implication of rare tumour subtypes in the WHO classification for EACs according to the classification for gastric cancer. Furthermore, claudin-6 positive tumors have shown promising efficacy of CAR T cell therapy in the recently published BNT-211-01 trial (NCT04503278). This represents a personalized therapeutic option for this tumor subtype.


Assuntos
Adenocarcinoma , Diferenciação Celular , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Feminino , Masculino , Idoso , Claudinas/metabolismo , Claudinas/genética , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética
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