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2.
Int J Mol Sci ; 25(6)2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38542465

RESUMEN

In this study, serum metabolic profiling of patients diagnosed with papillary thyroid carcinoma (PTC) and benign thyroid pathologies (BT) aimed to identify specific biomarkers and altered pathways when compared with healthy controls (C). The blood was collected after a histological confirmation from PTC (n = 24) and BT patients (n = 31) in parallel with healthy controls (n = 81). The untargeted metabolomics protocol was applied by UHPLC-QTOF-ESI+-MS analysis and the statistical analysis was performed using the MetaboAnalyst 5.0 platform. The partial least squares-discrimination analysis, including VIP values, random forest graphs, and heatmaps (p < 0.05), was complemented with biomarker analysis (with AUROC ranking) and pathway analysis, suggesting a model for abnormal metabolic pathways in PTC and BT based on 166 identified metabolites. There were 11 classes of putative biomarkers selected that were involved in altered metabolic pathways, e.g., polar molecules (amino acids and glycolysis metabolites, purines and pyrimidines, and selenium complexes) and lipids including free fatty acids, bile acids, acylated carnitines, corticosteroids, prostaglandins, and phospholipids. Specific biomarkers of discrimination were identified in each class of metabolites and upregulated or downregulated comparative to controls, PTC group, and BT group. The lipidomic window was revealed to be more relevant for finding biomarkers related to thyroid carcinoma or benign thyroid nodules, since our study reflected a stronger involvement of lipids and selenium-related molecules in metabolic discrimination.


Asunto(s)
Carcinoma Papilar , Selenio , Neoplasias de la Tiroides , Nódulo Tiroideo , Humanos , Carcinoma Papilar/metabolismo , Nódulo Tiroideo/diagnóstico , Cromatografía Líquida de Alta Presión , Neoplasias de la Tiroides/patología , Cáncer Papilar Tiroideo/diagnóstico , Cáncer Papilar Tiroideo/metabolismo , Metaboloma , Biomarcadores/metabolismo , Lípidos , Biomarcadores de Tumor/metabolismo
3.
Mod Pathol ; 37(4): 100438, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38278485

RESUMEN

We recently described novel dermal tumors with melanocytic differentiation and morphologic and biological similarities to cutaneous clear cell sarcoma, including CRTC1::TRIM11 cutaneous tumor, and clear cell tumors with melanocytic differentiation and either ACTIN::MITF or MITF::CREM. Here, we describe a series of 3 patients presenting with tumors reminiscent of CRTC1::TRIM11 cutaneous tumor, found to demonstrate a novel MED15::ATF1 fusion. All 3 patients were children (5-16 years old). Primary excision of case 1 showed a circumscribed wedge-shaped silhouette with peripheral intercalation into collagen fibers and scattered lymphoid aggregates. All 3 tumors abutted the epidermis; one showed a junctional component. Tumors were highly cellular and comprised of monomorphic, oval-to-round epithelioid cells arranged in vague nests and short fascicles in variably fibrotic stroma. Mitotic rate was high (hotspot 6-12/mm2), without atypical mitoses. Necrosis was focally present in case 3. All cases showed strong, diffuse nuclear staining for SOX10 and MITF (2/2) but showed variable expression for S100 protein (1/3) and other melanocytic markers-Melan-A (focal in 2/3), HMB45 (focal in 1/3), and Pan-Melanoma (patchy in 1/1). Whole-exome RNA sequencing demonstrated a MED15::ATF1 fusion without any other notable alterations. Cases 1 and 2 were completely excised without recurrence (12 months). Case 3 developed a grossly apparent regional lymph node spread shortly after primary biopsy. The patient was treated with wide excision, radiation, cervical lymph node dissection (4/46 with >75% lymph node replacement), and neoadjuvant and adjuvant nivolumab (alive without disease at cycle 11). This series is presented to aid in future diagnosis of this novel dermal tumor with melanocytic differentiation and emphasize the potential for aggressive biologic behavior, which should be considered in patient management planning.


Asunto(s)
Melanoma , Sarcoma de Células Claras , Neoplasias Cutáneas , Adolescente , Niño , Preescolar , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Complejo Mediador , Melanoma/diagnóstico , Sarcoma de Células Claras/diagnóstico , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patología , Neoplasias Cutáneas/patología , Factores de Transcripción/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética
4.
J Ethnopharmacol ; 322: 117590, 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38113986

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Shuangshen granules (SSG), a nationally patented Chinese medicinal formula, including Panax quinquefolium L., Panax notoginseng (Burkill) F. H. Chen, and Cordyceps sinensis (Berk.) Sacc., has demonstrated remarkable therapeutic effects on pancreatic cancer in clinical treatment for nearly 10 years. Previous pharmacological researches have found that its main components, including ginsenosides and cordycepin have anticancer or preventive effects on pancreatic ductal adenocarcinoma (PDAC), which may be associated with immune metabolism. However, the underlying pharmacological mechanism of SSG in the truncation effect of PDAC progression is still unclear. AIM OF THE STUDY: To comprehensively understand the infiltrating immune cells during the different stages of the PDAC development chain and search for immune-related biomarkers that could potentially serve as drug targets through bioinformatic analysis. Meanwhile, the truncation effect of SSG on PDAC progression was also investigated. MATERIALS AND METHODS: The gene expression profiles at different PDAC developmental stages, including normal pancreas, pancreatic intraepithelial neoplasia (PanIN), and PDAC, were retrieved from the GEO database. The GEO2R tool was used to identify differentially expressed genes among the three groups. Functional enrichment analysis was performed with the GSEA software and Metascape platform. The CIBERSORT algorithm evaluated immune cell infiltration in the three groups, and immune-related biomarkers were identified. Correlation analysis was employed to examine the association between immune cells and the biomarkers. One of these biomarkers was selected for immunohistochemistry validation in human samples. Lastly, the effectiveness of SSG against PDAC progression and the influence on the selected biomarker were validated in vivo. The underlying pharmacological mechanisms were also explored. RESULTS: One dataset was obtained, where the functional enrichment of DEGs primarily involved immune effector processes and cytokine production of immune cells. The differential immune cells reflected during the progression from PanIN to PDAC were B memory cells, monocytes, M2 macrophages, and activated dendritic cells. The upregulation of ACTA2 was closely associated with M2 macrophage regulation. The immunohistochemistry on human samples validated significant differences in ACTA2 expression levels as the PDAC progressed. Moreover, animal experiments revealed that the national patented drug SSG ameliorated the pathological changes, decreased the expression of ACTA2 and its functional protein α-smooth muscle actin during PDAC progression. The underlying pharmacological mechanism was related to the regulation of macrophage polarization and downregulation of TGF-ß/Smad signaling pathway. CONCLUSIONS: The immunosuppressive environment changes during the PDAC progression. ACTA2 is a potential immuned-target for drug prevention of PDAC, while SSG could be a promising drug candidate.


Asunto(s)
Carcinoma in Situ , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Humanos , Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patología , Biología Computacional , Medicamentos Herbarios Chinos
5.
FASEB J ; 37(11): e23271, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37882195

RESUMEN

Short-term recurrence of hepatocellular carcinoma (HCC) after radical resection leads to dismal outcomes. To screen high-recurrence risk patients to provide adjuvant treatment is necessary. Herein, based on our previous research, we further focused on the changes in the abundance of binuclear hepatocytes (ABH) in the paracancerous liver tissue to discuss the relationship between the attenuation of binuclear hepatocytes and postoperative short-term recurrence, by combining with the assessment of the value of a reported independent early recurrence risk factor in HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II). A cohort of 142 paracancerous liver tissues from HCC patients who received radical resection was collected. Binuclear hepatocytes were reduced in the paracancerous liver tissues, compared with the liver tissues from normal donors. ABH was negatively correlated with clinical features such as tumor size, TNM stages, tumor microsatellite formation, venous invasion, and Alpha-fetoprotein (AFP) level, as well as the expression of E2F7 and Anillin, which are two critical regulators concerning the hepatocyte polyploidization. According to the short-term recurrence information, ABH value was laminated, and univariate and multivariate logistic regression was performed to analyze the relationship between paracancerous ABH and short-term tumor relapse. Simultaneously, the predictive effectiveness of the ABH value was compared with the preoperative PIVKA-II value. As observed, the paracancerous ABH value below 1.5% was found to be an independent risk factor for recurrence. In conclusion, the paracancerous ABH is a credible indicator of short-term recurrence of HCC patients after radical resection, and regular assessment of ABH might help to prevent short-term HCC recurrence.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Biomarcadores , Hepatocitos/metabolismo , Protrombina , Biomarcadores de Tumor/metabolismo
6.
Free Radic Biol Med ; 209(Pt 1): 96-107, 2023 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-37838303

RESUMEN

High dose intravenous vitamin C (IVC) has been proposed as a pro-oxidant anticancer agent. However, there is a lack of biomarkers that are specific for this treatment. Here, we explored profiles of gene expression responding to IVC treatment in non-small cell lung cancer (NSCLC) cells as an effort for potential biomarker discovery. Genome-wide RNA-seq was performed in human NSCLC cell lines treated with pharmacological concentrations of vitamin C(VitC) for differential expression of genes. The identified genes were analyzed for correlations with patient prognosis using data from the Kaplan-Meier Plotter and the Human Protein Atlas databases. Further, tumor samples from a retrospective study of 153 NSCLC patients were analyzed with immunohistochemistry for expression of targeted genes, and patient prognosis was correlated to these genes. Two genes, namely SERPINE1 and SERPINB7 were found to be downregulated in NSCLC cells following VitC treatment. Combined patient data from the cohort analysis and online databases revealed that these 2 genes presented an unfavorable prognostic prediction of overall survival (OS) in NSCLC patients receiving standard of care. However, high expression level of these 2 genes were associated with prolonged OS in NSCLC patients receiving IVC in addition to standard of care. These data revealed that SERPINE1 and SERPINB7 have the potential to serve as predictive factors indicating favorable responses to IVC treatment in patients with NSCLC. Further validations are warranted.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Serpinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Ácido Ascórbico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Antineoplásicos/uso terapéutico , Serpinas/genética , Inhibidor 1 de Activador Plasminogénico/genética
7.
Int J Biol Macromol ; 245: 125308, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37315661

RESUMEN

Metastasis is one of the major causes for cancer mortality. Its early steps comprise of invasion of basement membrane and migration. Thus, it is hypothesized that a platform, that allows quantification and grading of migration capability of cells can potentially be used for predicting metastatic potential. Two-dimensional (2D) models have been rendered inadequate for modelling in-vivo microenvironment due to various reasons. To attenuate homogeneity observed in 2D, three-dimensional (3D) platforms supplemented with bioinspired components have been designed. Unfortunately, till date there are no simple models to capture the migration of cells in 3D along with quantification of the process. In this study, we report an alginate-collagen based 3D model system, which can predict the migratory property of the cells within 72 h. The micron size of the scaffold enabled faster readout and the optimum pore-size provided conducive cellular growth environment. The platform's ability to allow observation of cellular migration was validated by encapsulating cells with transiently upregulated matrix metalloprotease 9 (MMP9), which has been reported to play a significant role in migration of cells during metastasis. The readout for migration was clustering of cells in the microscaffolds detected in a short span of 48 h. The observed clustering in MMP9 upregulated cells was validated by observing changes in the epithelial-mesenchymal transition (EMT) markers. Thus, this simple 3D platform can be used to study migration and predict the metastatic potential of cells.


Asunto(s)
Alginatos , Movimiento Celular , Colágeno , Andamios del Tejido , Alginatos/química , Alginatos/metabolismo , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Colágeno/química , Colágeno/metabolismo , Transición Epitelial-Mesenquimal , Gelatina/metabolismo , Microfluídica , Metástasis de la Neoplasia , Porosidad , Andamios del Tejido/química , Factores de Transcripción Twist/metabolismo , Humanos , Línea Celular Tumoral
8.
Altern Ther Health Med ; 29(5): 132-140, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37023314

RESUMEN

Context: Paclitaxel (PTX) resistance is often associated with poor outcomes for patients with ovarian cancer (OC), but its mechanism is unknown. Clinicians are increasingly using immunotherapy in the management of OC, and the ability to assess tumor-immune interactions and identify effective, predictive, prognostic molecular biomarkers for OC is an urgent need. Objective: The study intended to explore the potential tumorigenesis mechanisms to identify promising biomarkers and improve survival in OC patients. Design: The research team performed a genetic analysis. Setting: The study took place at First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China. Outcome Measures: The research team: (1) obtained GSE66957 and GSE81778 gene expression profiles from the Gene Expression Omnibus (GEO) database and identified 468 differentially expressed genes (DEGs); (2) conducted functional enrichment analysis and constructed a protein-to-protein interaction (PPI) network; (3) identified the OC survival-related genes using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) webserver and compared those genes with upregulated DEGs to identify the core genes; (4) used GEPIA2 and the Kaplan-Meier plotter to explore the expression profiles and the prognostic values of the core genes in OC; (5) used the LinkOmics, Oncomine, and GEPIA2 web servers to perform co-expression analysis and explore functional networks correlated with keratin 7 (KRT7); (6) performed correlation analyses between KRT7, the six main types of tumor-infiltrating lymphocytes (TILs), and immune signatures, using the TIMER tool; and (7) subsequently detected the KRT7 expression in the cell lines IOSE80, A2780, A2780/PTX, ho8910, skov3, and ovcar3 using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) technology. Results: High expression levels of KRT7 were significantly correlated with progression-free survival (PFS) and poor overall survival (OS) for OC patients, with logrank P = .0074 and logrank P = .014, respectively. The expression levels of KRT7 were also significantly correlated with the infiltrated neutrophil levels (r = 0.169, P = .0077). The study identified neutrophils as potential predictors of survival in OC. Moreover, the expression levels of KRT7 in OC were positively correlated with 51 (31.68%) of the 161 immune gene markers. The RT-qPCR analyses revealed a high expression of KRT7 in the paclitaxel-resistant OC cell line. Conclusions: KRT7 is correlated with immune infiltration and paclitaxel resistance in OC patients. Therefore, clinicians could use KRT7 as a prognostic marker and a target in the development of new drugs.


Asunto(s)
Queratina-7 , Neoplasias Ováricas , Paclitaxel , Femenino , Humanos , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Queratina-7/genética , Queratina-7/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Paclitaxel/farmacología , Paclitaxel/uso terapéutico
9.
Int Immunopharmacol ; 114: 109518, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36502594

RESUMEN

BACKGROUND: ATP7A is an important copper transporter that regulates numerous cellular biological processes. However, the role of ATP7A in immunotherapy and targeted therapy, especially for hepatocellular carcinoma (HCC), remains unknown. METHODS: We analyzed ATP7A expression and its effect on digestive system tumor prognoses, assessed its expression in tissue microarrays from 319 HCC patients, and investigated the relationship between ATP7A expression and tumor immunity. Specifically, we evaluated the possible association between ATP7A and programmed death ligand 1 (PD-L1) expression in human HCC tissues. Finally, we analyzed the effect of ATP7A on sorafenib efficacy in HCC. RESULTS: ATP7A is generally highly expressed in digestive system tumors but related to poor prognosis only in HCC. ATP7A levels are positively associated with immune cell infiltration and immune checkpoint expression (especially PD-L1). HCC patients coexpressing APT7A and PD-L1 demonstrate poor prognoses. Moreover, HCC patients with high ATP7A levels were more sensitive to sorafenib and demonstrated higher survival rates after sorafenib treatment. CONCLUSIONS: This study provides insights into the correlation between ATP7A levels and tumor immune infiltration and immune checkpoint function in HCC, sheds light on the significance of ATP7A in cancer progression, and provides guidance for more effective and general therapeutic strategies.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Sorafenib/uso terapéutico , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proteínas Transportadoras de Cobre , Inmunoterapia , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , ATPasas Transportadoras de Cobre/genética , ATPasas Transportadoras de Cobre/metabolismo , Fragmentos de Péptidos/metabolismo
10.
Oxid Med Cell Longev ; 2022: 1507690, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36046688

RESUMEN

Background: Oxidative stress (OS) is associated with the development of acute myeloid leukemia (AML). However, there is lack of relevant research to confirm that OS-related genes can guide patients in risk stratification and predict their survival probability. Method: First, we Data from three public databases, respectively. Then, we use batch univariate Cox regression and machine learning to select important characteristic genes; next, we build the model and use receiver operating characteristic curve (ROC) to evaluate the accuracy. Moreover, GSEAs were performed to discover the molecular mechanism and conduct nomogram visualization. In addition, the relative importance value was used to identify the hub gene, and GSE9476 was to validate hub gene difference expression. Finally, we use symptom mapping to predict the candidate herbs, targeting the hub gene, and put these candidate herbs into Traditional Chinese Medicine Systems Pharmacology (TCMSP) to identify the main small molecular ingredients and then docking hub proteins with this small molecular. Results: A total of 313 candidate oxidative stress-related genes could affect patients' outcomes and machine learning to select six potential genes to construct a gene signature model to predict the overall survival (OS) of AML patients. Patients in a high group will obtain a short survival time when compared with the low-risk group (HR = 3.97, 95% CI: 2.48-6.36; p < 0.001). ROC results demonstrate the model has better prediction efficiency with AUC 0.873. GSEA suggests that this gene is enriched in several important signaling pathways. Nomogram is constructed and is robust. PLA2G4A is a hub gene of signature and associated with prognosis, and Nobiletin could target PLA2G4A for therapy AML. Conclusion: We use two different machine learning methods to build six oxidative stress-related gene signatures that could assist clinical decisions and identify PLA2G4A as a potential biomarker for AML. Nobiletin, targeting PLA2G4, may provide a third pathway for therapy AML.


Asunto(s)
Biomarcadores de Tumor , Leucemia Mieloide Aguda , Biomarcadores de Tumor/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Aprendizaje Automático , Nomogramas , Estrés Oxidativo/genética
11.
J Oleo Sci ; 71(10): 1481-1492, 2022 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-36089399

RESUMEN

Renal tissue plays a crucial function in maintaining homeostasis, making it vulnerable to xenobiotic toxicity. Pueraria montana has more beneficial potential against the various diseases and has long history used as a traditional Chinese medicine. But its effect against the renal cancer not scrutinize. The goal of this study is to see if Pueraria montana can protect rats from developing kidney tumors caused by diethylnitrosamine (DEN) and ferric nitrite (Fe-NTA). Wistar rats was selected for the current study and DEN (use as an inducer) and Fe-NTA (promoter) for induction the renal cancer. For 22 weeks, the rats were given orally Pueraria montana (12.5, 25, and 50 mg/kg) treatment. At regular intervals, the body weight and food intake were calculated. The rats were macroscopically evaluated for identification of cancer in the renal tissue. The renal tumor makers, renal parameters, antioxidant enzymes, phase I and II enzymes, inflammatory cytokines and mediators were estimated at end of the experimental study. Pueraria montana treated rats displayed the suppression of renal tumors, incidence of the tumors along with suppression of tumor percentage. Pueraria montana treated rats significantly (p < 0.001) increased body weight and suppressed the renal weight and food intake. It also reduced the level of renal tumor marker ornithine decarboxylase (ODC) and [3H] thymidine incorporation along with suppression of renal parameter such as uric acid, blood urea nitrogen (BUN), urea and creatinine. Pueraria montana treatment significantly (p < 0.001) altered the level of phase enzymes and antioxidant. Pueraria montana treatment significantly (p < 0.001) repressed the level of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and improved the level of interleukin-10 (IL-10). Pueraria montana treatment suppressed the level of prostaglandin (PGE2), cyclooxygenase-2 (COX-2), nuclear kappa B factor (NF-κB) and transforming growth factor beta 1 (TGF-ß1). Pueraria montana suppressed the inflammatory necrosis, size the bowman capsules in the renal histopathology. Pueraria montana exhibited the chemoprotective effect via dual mechanism such as suppression of inflammatory reaction and oxidative stress.


Asunto(s)
Neoplasias Renales , Pueraria , Animales , Antioxidantes/farmacología , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/farmacología , Peso Corporal , Creatinina/farmacología , Ciclooxigenasa 2/metabolismo , Dietilnitrosamina/farmacología , Compuestos Férricos , Inflamación/tratamiento farmacológico , Interleucina-10 , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Neoplasias Renales/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , FN-kappa B/metabolismo , Ácido Nitrilotriacético/análogos & derivados , Nitritos/farmacología , Ornitina Descarboxilasa/metabolismo , Ornitina Descarboxilasa/farmacología , Estrés Oxidativo , Prostaglandinas , Prostaglandinas E/metabolismo , Prostaglandinas E/farmacología , Pueraria/metabolismo , Ratas , Ratas Wistar , Timidina/metabolismo , Timidina/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Urea , Ácido Úrico/farmacología , Xenobióticos/farmacología
12.
J Mol Diagn ; 24(7): 775-783, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35526835

RESUMEN

Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization assay. However, current HER2 testing methods are designed to identify HER2-amplified tumors with high expression levels. The true definition of HER2-low expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. Erb-B2 receptor tyrosine kinase 2 (ERBB2) mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI, 0.36-0.57), 0.58 (95% CI, 0.26-0.70), and 0.32 (95% CI, -0.12 to 0.75) when comparing IHC 0+ without staining versus IHC 0+ with some staining, IHC 0+ with some staining versus IHC 1+, and IHC 1+ versus IHC 2+/fluorescence in situ hybridization-negative, respectively. The results showed immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggests a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response needs to be further evaluated by prospective clinical trials.


Asunto(s)
Neoplasias de la Mama , Receptor ErbB-2 , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ/métodos , Estudios Prospectivos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
13.
Surg Pathol Clin ; 15(1): 105-120, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35236627

RESUMEN

Predictive biomarker testing on metastatic breast cancer is essential for determining patient eligibility for targeted therapeutics. The National Comprehensive Cancer Network currently recommends assessment of specific biomarkers on metastatic tumor subtypes, including hormone receptors, HER2, and BRCA1/2 mutations, on all newly metastatic breast cancers subtypes; programmed death-ligand 1 on metastatic triple-negative carcinomas; and PIK3CA mutation status on estrogen receptor-positive carcinomas. In select circumstances mismatch repair protein deficiency and/or microsatellite insufficiency, tumor mutation burden, and NTRK translocation status are also testing options. Novel biomarker testing, such as detecting PIK3CA mutations in circulating tumor DNA, is expanding in this rapidly evolving arena.


Asunto(s)
Neoplasias de la Mama , Carcinoma , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Carcinoma/genética , Femenino , Humanos , Mutación
14.
Int J Mol Sci ; 23(5)2022 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-35269569

RESUMEN

Cancer stem cells (CSCs) are a small subpopulation of tumor cells harboring properties that include self-renewal, multi-lineage differentiation, tumor reconstitution, drug resistance and invasiveness, making them key players in tumor relapse. In the present paper, we develop new CSC models and analyze the molecular pathways involved in survival to identify targets for the establishment of novel therapies. Endometrial carcinoma-derived stem-like cells (ECSCs) were isolated from carcinogenic gynecological tissue and analyzed regarding their expression of prominent CSC markers. Further, they were treated with the MYC-signaling inhibitor KJ-Pyr-9, chemotherapeutic agent carboplatin and type II diabetes medication metformin. ECSC populations express common CSC markers, such as Prominin-1 and CD44 antigen as well as epithelial-to-mesenchymal transition markers, Twist, Snail and Slug, and exhibit the ability to form free-floating spheres. The inhibition of MYC signaling and treatment with carboplatin as well as metformin significantly reduced the cell survival of ECSC-like cells. Further, treatment with metformin significantly decreased the mitochondrial membrane potential of ECSC-like cells, while the extracellular lactate concentration was increased. The established ECSC-like populations represent promising in vitro models to further study the contribution of ECSCs to endometrial carcinogenesis. Targeting MYC signaling as well as mitochondrial bioenergetics has shown promising results in the diminishment of ECSCs, although molecular signaling pathways need further investigations.


Asunto(s)
Carboplatino/farmacología , Neoplasias Endometriales/metabolismo , Metformina/farmacología , Mitocondrias/metabolismo , Células Madre Neoplásicas/citología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Piridinas/farmacología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mitocondrias/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Transducción de Señal/efectos de los fármacos
15.
Cell Mol Life Sci ; 79(2): 116, 2022 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-35113247

RESUMEN

Esophageal cancer (EC) is one of the most incident and lethal tumors worldwide. Although surgical resection is an important approach in EC treatment, late diagnosis, metastasis and recurrence after surgery have led to the management of adjuvant and neoadjuvant therapies over the past few decades. In this scenario, 5-fluorouracil (5-FU) and cisplatin (CISP), and more recently paclitaxel (PTX) and carboplatin (CBP), have been traditionally used in EC treatment. However, chemoresistance to these agents along EC therapeutic management represents the main obstacle to successfully treat this malignancy. In this sense, despite the fact that most of chemotherapy drugs were discovered several decades ago, in many cases, including EC, they still represent the most affordable and widely employed treatment approach for these tumors. Therefore, this review summarizes the main mechanisms through which the response to the most widely chemotherapeutic agents used in EC treatment is impaired, such as drug metabolism, apoptosis resistance, cancer stem cells (CSCs), cell cycle, autophagy, energetic metabolism deregulation, tumor microenvironment and epigenetic modifications.


Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Mutación , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Esofágicas/metabolismo , Fluorouracilo/uso terapéutico , Humanos , Terapia Molecular Dirigida/métodos , Paclitaxel/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética
16.
Aging (Albany NY) ; 14(2): 826-844, 2022 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-35042833

RESUMEN

BACKGROUND: Evidence from research supports the significant role of alternative polyadenylation (APA) in the development of cancer. The aim of this study is to explore the prognostic and therapeutic value of APA events for patients with low-grade gliomas (LGG). METHODS: The gene expression and APA profiles of patients with low-grade gliomas were obtained from The Cancer Genome Atlas database. All patients were sorted randomly into training and test sets. The prognostic-associated events of alternative splicing were screened by univariate Cox regression. Subsequently, Least Absolute Shrinkage and Selection Operator and multivariate Cox analysis were performed to construct a prognostic signature. The patients were sorted into the high and low-risk groups based on their median risk score. Bioinformatics methods were used to identify genetic variation, pathway activation, immune heterogeneity, and drug response differences between the two groups. RESULTS: A prognostic signature was constructed shown to be capable of accurately predicting prognosis of patients with LGG. Notable variations were observed in the tumor mutation burden and copy number variations between the high-risk and low-risk patients. Besides, the high-risk group had enhanced immune cell abundance and immune checkpoint gene expression. In terms of drug response, we further found that the patients of high-risk group were more sensitive to immunotherapy, but chemotherapy was suggestively more appropriate for the low-risk group patients. CONCLUSION: Our findings give new insights and methods related to prognosis prediction and treatment methods for LGG patients, and expand the understanding regarding the role of alternative splicing in LGG.


Asunto(s)
Glioma , Poliadenilación , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Variaciones en el Número de Copia de ADN , Glioma/genética , Glioma/metabolismo , Glioma/terapia , Humanos , Poliadenilación/genética , Pronóstico
17.
Clin Breast Cancer ; 22(4): e576-e585, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35027319

RESUMEN

Apocrine carcinoma of the breast is a rare malignancy. According to 2019 WHO classification, apocrine cellular features and a characteristic steroid receptor profile (Estrogen receptor (ER)-negative and androgen receptor (AR)-positive) define apocrine carcinoma. Her-2/neu protein expression is reported in ∼30-50% of apocrine carcinomas, while NGS analysis showed frequent PIK3CA/PTEN/AKT and TP53 mutations Followed by deregulation in the mitogen-activated protein kinase pathway components (mutations of KRAS, NRAS, BRAF). A recent miRNA study indicates various miRNAs (downregulated hsa-miR-145-5p and upregulated 14 miRNAs such as hsa-miR-182-5p, hsa-miR-3135b, and hsa-miR-4417) may target the commonly altered pathways in apocrine carcinomas such as ERBB2/HER2 and mitogen-activated protein kinase signaling pathway. Although AR expression is a hallmark of apocrine carcinoma, little is known regarding the efficacy/resistance to antiandrogens. Success of bicalutamide, a non-steroidal anti-androgen, was reported in a case of Her2-negative apocrine carcinoma. Two recent studies, however, described presence of anti-androgen resistance biomarkers (a splice variant ARv7 and AR/NCOA2 co-amplification) in a subset of AR+ apocrine carcinomas, cautioning the use of anti-androgens in AR+ triple-negative breast carcinomas. Apocrine carcinomas rarely show biomarkers predictive of response to immune checkpoint inhibitors (PD-L1 expression, MSI-H status, and TMB-high). Therefore, a comprehensive cancer profiling of apocrine carcinomas is necessary to identify potential therapeutic targets for a truly individualized treatment approach.


Asunto(s)
Neoplasias de la Mama , Carcinoma , MicroARNs , Neoplasias de las Glándulas Sudoríparas , Neoplasias de la Mama Triple Negativas , Glándulas Apocrinas/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Carcinoma/patología , Femenino , Humanos , Inmunohistoquímica , MicroARNs/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Neoplasias de las Glándulas Sudoríparas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
18.
Oncology ; 100(2): 65-73, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34844247

RESUMEN

BACKGROUND/AIM: With the development of systemic treatment methods for unresectable hepatocellular carcinoma (uHCC), the concept of unsuitable for transcatheter arterial chemoembolization (TACE) has become important. This study aimed to establish a simple predictive scoring system for determining TACE unsuitable status. MATERIALS/METHODS: From 1998 to 2015, 196 patients with intermediate-stage uHCC with Child-Pugh A (score 5:6 = 108:88) and given TACE as the initial treatment were enrolled. At the baseline, tumor burden (Milan criteria-out, up-to-7 in/out, and up-to-11 in/out: 0-2 points) and modified albumin-bilirubin grade 1/2a or 2b (0-1 point) were added to determine the score for TACE unsuitable (CITRUS-MICAN score; low <2 and high ≥2). In addition, a previously reported tumor marker (TM) score, in which alpha-fetoprotein (AFP) was ≥100 ng/mL, fucosylated AFP ≥10%, and des-gamma-carboxy prothrombin ≥100 mAU/mL (each 1 point) (total 0, 1, or ≥2 points), was used for additionally evaluating tumor malignancy potential. Prognosis was retrospectively evaluated based on those scores. RESULTS: Median survival time (MST) was better for low compared to high CITRUS-MICAN score (42.0 vs. 26.4 months) (p = 0.002). A 2-step evaluation using the combination of CITRUS-MICAN and TM scores showed an MST of 43.2 months for low CITRUS-MICAN/TM score 0/1 (rank-A) and 39.6 months for low CITRUS-MICAN/TM score ≥2 (rank-B2), while it was 46.8 months for high CITRUS-MICAN/TM score 0 (rank-B1), 28.8 months for high CITRUS-MICAN/TM score 1 (rank-B2), and 22.8 months for high CITRUS-MICAN/TM score ≥2 (rank-C). For rank-A cases (n = 51), MST was 43.2 months, while it was 46.8 months for rank-B1 (n = 12), 31.2 months for rank-B2 (n = 82), and 22.8 months for rank-C (n = 51) (p = 0.001). CONCLUSION: The results showed that rank-C indicates absolute TACE unsuitable status. For rank-A patients, good prognosis with TACE can be expected, while TACE refractoriness status during the clinical course should be carefully evaluated so as to anticipate the appropriate timing for switching to systemic treatment in rank-B1 and -B2 patients.


Asunto(s)
Albúminas/metabolismo , Bilirrubina/metabolismo , Biomarcadores/metabolismo , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Precursores de Proteínas/metabolismo , Protrombina/metabolismo , alfa-Fetoproteínas/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Quimioembolización Terapéutica , Femenino , Humanos , Japón , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia
19.
Radiology ; 302(2): 410-418, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34751617

RESUMEN

Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Inositol/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Biomarcadores de Tumor/metabolismo , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Valor Predictivo de las Pruebas , Estudios Prospectivos , Insuficiencia del Tratamiento
20.
Nat Rev Drug Discov ; 21(2): 99-114, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34702990

RESUMEN

Recent progress in understanding the molecular basis of cellular processes, identification of promising therapeutic targets and evolution of the regulatory landscape makes this an exciting and unprecedented time to be in the field of oncology drug development. However, high costs, long development timelines and steep rates of attrition continue to afflict the drug development process. Lack of predictive preclinical models is considered one of the key reasons for the high rate of attrition in oncology. Generating meaningful and predictive results preclinically requires a firm grasp of the relevant biological questions and alignment of the model systems that mirror the patient context. In doing so, the ability to conduct both forward translation, the process of implementing basic research discoveries into practice, as well as reverse translation, the process of elucidating the mechanistic basis of clinical observations, greatly enhances our ability to develop effective anticancer treatments. In this Review, we outline issues in preclinical-to-clinical translatability of molecularly targeted cancer therapies, present concepts and examples of successful reverse translation, and highlight the need to better align tumour biology in patients with preclinical model systems including tracking of strengths and weaknesses of preclinical models throughout programme development.


Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Desarrollo de Medicamentos , Evaluación Preclínica de Medicamentos/métodos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Animales , Biomarcadores de Tumor/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología
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