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1.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800786

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical techniques and new (neo)adjuvant chemotherapy regimens. Early detection of PDAC may increase the overall survival. It is furthermore foreseen that precision medicine will provide improved prognostic stratification and prediction of therapeutic response. In this review, omics-based discovery efforts are presented that aim for novel diagnostic and prognostic biomarkers of PDAC. For this purpose, we systematically evaluated the literature published between 1999 and 2020 with a focus on protein- and protein-glycosylation biomarkers in pancreatic cancer patients. Besides genomic and transcriptomic approaches, mass spectrometry (MS)-based proteomics and glycomics of blood- and tissue-derived samples from PDAC patients have yielded new candidates with biomarker potential. However, for reasons discussed in this review, the validation and clinical translation of these candidate markers has not been successful. Consequently, there has been a change of mindset from initial efforts to identify new unimarkers into the current hypothesis that a combination of biomarkers better suits a diagnostic or prognostic panel. With continuing development of current research methods and available techniques combined with careful study designs, new biomarkers could contribute to improved detection, prognosis, and prediction of pancreatic cancer.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/diagnóstico , Glicômica/métodos , Glicoproteínas/análise , Espectrometria de Massas/métodos , Proteínas de Neoplasias/análise , Neoplasias Pancreáticas/diagnóstico , Proteômica/métodos , Líquidos Corporais/química , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Tomada de Decisão Clínica , Diagnóstico Diferencial , Detecção Precoce de Câncer , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Pancreatite Crônica/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Medicina de Precisão , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco
2.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800799

RESUMO

Liquid biopsies constitute a minimally invasive means of managing cancer patients, entailing early diagnosis, follow-up and prediction of response to therapy. Their use in the germ cell tumor field is invaluable since diagnostic tissue biopsies (which are invasive) are often not performed, and therefore only a presumptive diagnosis can be made, confirmed upon examination of the surgical specimen. Herein, we provide an overall review of the current liquid biopsy-based biomarkers of this disease, including the classical, routinely used serum tumor markers-the promising microRNAs rapidly approaching the introduction into clinical practice-but also cell-free DNA markers (including DNA methylation) and circulating tumor cells. Finally, and importantly, we also explore novel strategies and challenges for liquid biopsy markers and methodologies, providing a critical view of the future directions for liquid biopsy tests in this field, highlighting gaps and unanswered questions.


Assuntos
Biópsia Líquida , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Procedimentos Clínicos , DNA de Neoplasias/química , Gerenciamento Clínico , Feminino , Humanos , Masculino , MicroRNAs/análise , Proteínas de Neoplasias/análise , Neoplasias Embrionárias de Células Germinativas/sangue , Neoplasias Embrionárias de Células Germinativas/química , Neoplasias Embrionárias de Células Germinativas/patologia , Células Neoplásicas Circulantes , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , RNA Neoplásico/análise , Neoplasias Testiculares/sangue , Neoplasias Testiculares/química , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/patologia
3.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540684

RESUMO

N6-methyladenosine (m6A) modification on RNA plays an important role in tumorigenesis and metastasis, which could change gene expression and even function at multiple levels such as RNA splicing, stability, translocation, and translation. In this study, we aim to conduct a comprehensive analysis on m6A RNA methylation-related genes, including m6A RNA methylation regulators and m6A RNA methylation-modified genes, in liver hepatocellular carcinoma, and their relationship with survival and clinical features. Data, which consist of the expression of widely reported m6A RNA methylation-related genes in liver hepatocellular carcinoma from The Cancer Genome Atlas (TCGA), were analyzed by one-way ANOVA, Univariate Cox regression, a protein-protein interaction network, gene enrichment analysis, feature screening, a risk prognostic model, correlation analysis, and consensus clustering analysis. In total, 405 of the m6A RNA methylation-related genes were found based on one-way ANOVA. Among them, DNA topoisomerase 2-alpha (TOP2A), exodeoxyribonuclease 1 (EXO1), ser-ine/threonine-protein kinase Nek2 (NEK2), baculoviral IAP repeat-containing protein 5 (BIRC5), hyaluronan mediated motility receptor (HMMR), structural maintenance of chromosomes protein 4 (SMC4), bloom syndrome protein (BLM), ca-sein kinase I isoform epsilon (CSNK1E), cytoskeleton-associated protein 5 (CKAP5), and inner centromere protein (INCENP), which were m6A RNA methylation-modified genes, were recognized as the hub genes based on the protein-protein interaction analysis. The risk prognostic model showed that gender, AJCC stage, grade, T, and N were significantly different between the subgroup with the high and low risk groups. The AUC, the evaluation parameter of the prediction model which was built by RandomForest, was 0.7. Furthermore, two subgroups were divided by consensus clustering analysis, in which stage, grade, and T differed. We identified the important genes expressed significantly among two clusters, including uridine-cytidine kinase 2 (UCK2), filensin (BFSP1), tubulin-specific chaperone D (TBCD), histone-lysine N-methyltransferase PRDM16 (PRDM16), phosphorylase b ki-nase regulatory subunit alpha (PHKA2), serine/threonine-protein kinase BRSK2 (BRSK2), Arf-GAP with coiled-coil (ACAP3), general transcription factor 3C polypep-tide 2 (GTF3C2), and guanine nucleotide exchange factor MSS4 (RABIF). In our study, the m6A RNA methylation-related genes in liver hepatocellular carcinoma were analyzed systematically, including the expression, interaction, function, and prognostic values, which provided an important theoretical basis for m6A RNA methylation in liver cancer. The nine important m6A-related genes could be prognostic markers in the survival time of patients.


Assuntos
Adenosina/análogos & derivados , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Mapas de Interação de Proteínas , RNA/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Metilação , Modelos Biológicos , Proteínas de Neoplasias/análise , Prognóstico , RNA/química , Análise de Sequência de RNA
4.
Int J Mol Sci ; 22(2)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435254

RESUMO

Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related mortality in women worldwide. Breast cancer is fairly heterogeneous and reveals six molecular subtypes: luminal A, luminal B, HER2+, basal-like subtype (ER-, PR-, and HER2-), normal breast-like, and claudin-low. Breast cancer screening and early diagnosis play critical roles in improving therapeutic outcomes and prognosis. Mammography is currently the main commercially available detection method for breast cancer; however, it has numerous limitations. Therefore, reliable noninvasive diagnostic and prognostic biomarkers are required. Biomarkers used in cancer range from macromolecules, such as DNA, RNA, and proteins, to whole cells. Biomarkers for cancer risk, diagnosis, proliferation, metastasis, drug resistance, and prognosis have been identified in breast cancer. In addition, there is currently a greater demand for personalized or precise treatments; moreover, the identification of novel biomarkers to further the development of new drugs is urgently needed. In this review, we summarize and focus on the recent discoveries of promising macromolecules and cell-based biomarkers for the diagnosis and prognosis of breast cancer and provide implications for therapeutic strategies.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Terapia Baseada em Transplante de Células e Tecidos , Detecção Precoce de Câncer , Feminino , Humanos , Imunoterapia , Proteínas de Neoplasias/análise , Prognóstico
6.
Ann Hematol ; 99(10): 2449-2451, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32851455
7.
Tunis Med ; 98(2): 168-171, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32395809

RESUMO

BACKGROUND: Mammary analogue secretory carcinoma is a rare new entity of low-grade malignant tumor of salivary glands. It shared the same histologic features and the chromosomal translocation t(12;15)(p13;q25) as secretory carcinoma of the breast. AIM: To highlight the diagnosis approaches and the attitude of management in a case of MASC which is the first case reported in Tunisia. Reported case: A case of MASC of the lower left jugal mucosa was reviewed for its microscopic and immunohistochemical features. Fluorescence in situ hybridization (FISH) for the ETV6-NTRK3 translocation was performed. Surgery was the only treatment required in this case. No signs of local or regional recurrence during the one-year follow-up were noticed. COMMENTARIES: Secretory carcinoma was confused with other salivary gland tumors especially acinic cell carcinoma due to their morphological similarities, making diagnosis dilemma. Fluorescence in-situ hybridization (FISH) is the one definitive finding to confirm the diagnosis of MASC and to differentiate it from the other types of salivary gland tumor. At the present time, no specific therapy is available for patients with MASC.


Assuntos
Carcinoma Secretor Análogo ao Mamário/diagnóstico , Anoctamina-1/análise , Anoctamina-1/metabolismo , Bochecha/patologia , Análise Citogenética , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Mamoglobina A/análise , Mamoglobina A/metabolismo , Carcinoma Secretor Análogo ao Mamário/genética , Carcinoma Secretor Análogo ao Mamário/cirurgia , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Proteínas S100/análise , Proteínas S100/metabolismo , Tunísia
8.
Jpn J Clin Oncol ; 50(6): 671-678, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32129446

RESUMO

OBJECTIVE: Multidrug resistance and consequent relapse are two major obstacles for treating children with acute lymphoblastic leukemia, the most frequent childhood malignancy. MicroRNAs have potential regulatory roles in response to chemotherapy. The goal of this study was to determine the microRNA that may have effects on the expression level of brain and acute lymphoblastic leukemia (BAALC) and to investigate the in vitro and ex vivo association between their expression levels. METHODS: In silico tools were utilized to determine a putative miRNA targeting BALLC. Quantitative real-time polymerase chain reaction was used to investigate expression levels of BAALC and its predicted microRNA, miR-326, in bone marrow samples of 30 children with acute lymphoblastic leukemia and 13 controls, in addition to the resistant and parental CCRF-CEM cell lines. To assess the status of response to therapy, minimal residual disease was measured using single-strand conformation polymorphism. RESULTS: MiR-326 was selected due to the strong possibility of its interaction with BAALC according to the obtained in silico results. Statistical analysis showed a significant downregulation of miR-326 and overexpression of BALLC in drug-resistant acute lymphoblastic leukemia cell line and patients compared with the parental cell line and drug-sensitive patients, respectively (P = 0.015, 0.005, 0.0484 and 0.0005, respectively). The expression profiles of miR-326 and BAALC were inversely correlated (P = 0.028). CONCLUSIONS: The results introduced the inversely combined expression levels of miR-326 and BAALC as a novel, independent prognostic biomarker for pediatric acute lymphoblastic leukemia (P = 0.007). Moreover, bioinformatics data showed a possible regulatory role for miR-326 on BAALC mRNA, which may possibly contribute to the development of drug resistance in patients with childhood acute lymphoblastic leukemia.


Assuntos
Biomarcadores/análise , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Medula Óssea/metabolismo , Linhagem Celular Tumoral , Criança , Pré-Escolar , Simulação por Computador , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , MicroRNAs/análise , MicroRNAs/metabolismo , Proteínas de Neoplasias/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
9.
Bull Cancer ; 107(4): 410-416, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145962

RESUMO

Tumor profiling has been shown to benefit patients with rare or refractory metastatic cancer, but several limitations hamper its use in daily clinical practice. We aim to assess the added benefit of a comprehensive tumor profiling, including factors predictive of response to targeted and cytotoxic therapy, in the treatment of refractory or rare solid tumors outside of a formal clinical trial. Patients were included between 2013 and 2017. Multiplatform comprehensive tumor profiling (CTP) was performed on FFPE specimens. Tumor response was evaluated by imaging using the RECIST criteria version 1.1. The PFS ratio was defined as PFS under CTP-guided therapy (PFS2)/PFS under previous standard therapy (PFS1). A clinical benefit was identified if the PFS ratio exceeded the 1.3 threshold value. In total, 184 patients were enrolled among whom 104 were evaluable for the PFS ratio. Objective response rates (ORR) were equal to 25% (CI95: 16.6-33.4%) and 36.5% (CI95: 27.2-45.8%) on the last therapy before CTP and on the CTP-guided therapy respectively (P-value=0.058 on paired proportion comparison test). The proportion of patients achieving a PFS2/PFS1 ratio≥1.3 was equal to 50%. The median PFS1 was statistically lower than PFS2 (120 days compared to 184 days respectively, P-value log rank 0.01). These results confirm the feasibility and the added benefit of a CTP in patients with refractory tumors in daily clinical practice especially in patients not able to enter a clinical trial.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Doenças Raras/tratamento farmacológico , Doenças Raras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/antagonistas & inibidores , Tomada de Decisão Clínica , Estudos de Viabilidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização In Situ/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/mortalidade , Probabilidade , Intervalo Livre de Progressão , Análise Serial de Proteínas/métodos , Doenças Raras/mortalidade , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Adulto Jovem
10.
Neoplasma ; 67(3): 707-713, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32202903

RESUMO

The clinical value of synuclein-γ (SNCG) in oral squamous cell carcinoma (OSCC) was evaluated by detecting the expression of SNCG in saliva and tissues and its correlation with clinicopathological parameters (age, gender, ethnicity, degree of differentiation, clinical stage, and lymph node metastasis). Salivary samples were collected from 79 patients with OSCC, 31 patients with oral premalignant lesions (OPMLs), such as oral lichen planus, oral leukoplakia, and erythema, and 80 controls, and levels of SNCG in salivary samples were determined by enzyme-linked immunosorbent assay (ELISA). Tissue expression in formalin-fixed tissue biopsies of 94 cases of OSCC and 30 adjacent normal tissues was analyzed by immunohistochemistry (IHC) using an antibody against SNCG. The results showed that the salivary levels of SNCG in patients with OSCC and OPMLs were significantly higher than those detected in the control group (p<0.001). The immunohistochemical results showed that SNCG was highly expressed in tumor cells of OSCC patients, with low expression in the adjacent normal epithelium (p<0.001, OR=6.074). Salivary SNCG level correlated with differentiation (p=0.022). Besides, the expression of SNCG in OSCC tissues was also significantly associated with differentiation (p<0.001).


Assuntos
Carcinoma de Células Escamosas/química , Neoplasias Bucais/química , Proteínas de Neoplasias/análise , Saliva/química , gama-Sinucleína/análise , Anticorpos Monoclonais , Biomarcadores Tumorais/análise , Humanos , Imuno-Histoquímica
11.
Acta Biochim Biophys Sin (Shanghai) ; 52(2): 168-179, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32047913

RESUMO

Y-box binding protein 1 (YB-1) is manifested as its involvement in cell proliferation and differentiation and malignant cell transformation. Overexpression of YB-1 is associated with glioma progression and patient survival. The aim of this study is to investigate the influence of YB-1 knockdown on glioma cell progression and reveal the mechanisms of YB-1 knockdown on glioma cell growth, migration, and apoptosis. It was found that the knockdown of YB-1 decreased the mRNA and protein levels of YB-1 in U251 glioma cells. The knockdown of YB-1 significantly inhibited cell proliferation, colony formation, and migration in vitro and tumor growth in vivo. Proteome and phosphoproteome data revealed that YB-1 is involved in glioma progression through regulating the expression and phosphorylation of major proteins involved in cell cycle, adhesion, and apoptosis. The main regulated proteins included CCNB1, CCNDBP1, CDK2, CDK3, ADGRG1, CDH-2, MMP14, AIFM1, HO-1, and BAX. Furthermore, it was also found that YB-1 knockdown is associated with the hypo-phosphorylation of ErbB, mTOR, HIF-1, cGMP-PKG, and insulin signaling pathways, and proteoglycans in cancer. Our findings indicated that YB-1 plays a key role in glioma progression in multiple ways, including regulating the expression and phosphorylation of major proteins associated with cell cycle, adhesion, and apoptosis.


Assuntos
Glioma/patologia , Proteína 1 de Ligação a Y-Box/deficiência , Apoptose , Proteínas Reguladoras de Apoptose/análise , Proteínas Reguladoras de Apoptose/metabolismo , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/metabolismo , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/metabolismo , Fosforilação , Proteômica , RNA Neoplásico/análise , Proteína 1 de Ligação a Y-Box/genética
12.
Sci Rep ; 10(1): 2105, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034162

RESUMO

Biological reconstruction of allografts and recycled autografts have been widely implemented in high-grade osteogenic sarcoma. For treating tumor-bearing autografts, extracorporeal irradiation (ECIR) and liquid nitrogen (LN) freezing techniques are being used worldwide as a gold standard treatment procedure. Both the methods aim to eradicate the tumor cells from the local recurrence and restore the limb function. Therefore, it is essential and crucial to find, and compare the alterations at molecular and physiological levels of the treated and untreated OGS recycled autografts to obtain valuable clinical information for better clinical practice. Thus, we aimed to investigate the significantly expressed altered proteins from ECIR-and cryotherapy/freezing- treated OGS (n = 12) were compared to untreated OGS (n = 12) samples using LC-ESI-MS/MS analysis, and the selected proteins from this protein panel were verified using immunoblot analysis. From our comparative proteomic analysis identified a total of 131 differentially expressed proteins (DEPs) from OGS. Among these, 91 proteins were up-regulated (2.5 to 3.5-folds), and 40 proteins were down-regulated (0.2 to 0.5 folds) (p < 0.01 and 0.05). The functional enrichment analysis revealed that the identified DEPs have belonged to more than 10 different protein categories include cytoskeletal, extracellular matrix, immune, enzyme modulators, and cell signaling molecules. Among these, we have confirmed two potential candidates' expressions levels such as Fibronectin and Protein S100 A4 using western blot analysis. Our proteomic study revealed that LN-freezing and ECIR treatments are effectively eradicating tumor cells, and reducing the higher expressions of DEPs at molecular levels which may help in restoring the limb functions of OGS autografts effectively. To the best of our knowledge, this is the first proteomic study that compared proteomic profiles among freezing, ECIR treated with untreated OGS in recycled autografts. Moreover, the verified proteins could be used as prognostic or diagnostic markers that reveal valuable scientific information which may open various therapeutic avenues in clinical practice to improve patient outcomes.


Assuntos
Neoplasias Ósseas/diagnóstico , Crioterapia , Osteossarcoma/diagnóstico , Proteoma/análise , Adulto , Idoso , Biomarcadores Tumorais/análise , Western Blotting , Neoplasias Ósseas/química , Neoplasias Ósseas/terapia , Terapia Combinada , Crioterapia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Osteossarcoma/química , Osteossarcoma/terapia , Adulto Jovem
13.
Medicina (Kaunas) ; 56(2)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019121

RESUMO

BACKGROUND AND OBJECTIVES: Patients with oral squamous cell carcinoma (OSCC), a common malignancy in Asian countries, have a poor prognosis. We investigated the role of Krüppel-like factor 17 (KLF17) and its prognostic significance in OSCC. MATERIALS AND METHODS: KLF17 expression was measured by immunohistochemical staining of specimens from 283 patients with OSCC. We analyzed correlations between KLF17 expression and clinicopathologic features and between KLF17 expression and overall survival. The prognostic value of KLF17 was tested using Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: Among the 283 patients, high KLF17 expression was significantly associated with an early OSCC stage and low T-value (p = 0.033 and p = 0.036, respectively). The five-year survival rates were better in patients with high KLF17 expression than with low expression (66.5% and 49.6%, respectively). The prognostic role of KLF17 was further confirmed through multivariate analysis (hazard ratio 1.506, 95% confidence interval 1.034-2.191, p = 0.033). The prognostic value was more significant in patients with a history of betel quid chewing or with a low T-value. CONCLUSIONS: High KLF17 expression can serve as a marker for a favorable prognosis in patients with OSCC. The prognostic role of KLF17 is more significant in patients with a history of betel quid chewing or a low T-value.


Assuntos
Carcinoma de Células Escamosas/química , Neoplasias Bucais/química , Proteínas de Neoplasias/análise , Fatores de Transcrição/análise , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalos de Confiança , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida
14.
Hum Pathol ; 98: 89-97, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035991

RESUMO

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. Differences inprognosis can be noted owing to the tumor grade determined using multiple grading schemes (2-tier: low- and high-grade vs. 3-tier: low-, intermediate-, and high-grade). We studied clinicopathologic features of MEC using a 3-tier grading system and retrospectively categorized cytologic diagnoses as per the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC).A total of 69 cases of MEC were identified, and most were seen in the parotid gland. Aggressive clinical behavior was seen in high-grade MEC compared with intermediate- and low-grade MEC. By fluorescence in situ hybridization (FISH) analysis, MAML2 rearrangements were seen in 78% of cases.The MSRSGC subcategorized the majority (63.8%) of MEC as salivary gland neoplasm of uncertain malignant potential, suspicious for malignancy, or malignant. Clustering intermediate- with low-grade cases did not significantly impact the clinical behavior. Both high-grade and oncocytic MEC can be MAML2 FISH negative.


Assuntos
Carcinoma Mucoepidermoide/patologia , Gradação de Tumores , Neoplasias das Glândulas Salivares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anoctamina-1/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Carcinoma Mucoepidermoide/química , Carcinoma Mucoepidermoide/genética , Feminino , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/química , Neoplasias das Glândulas Salivares/genética , Transativadores/genética , Adulto Jovem
15.
Blood Adv ; 4(2): 367-379, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31985806

RESUMO

Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominantly within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy-induced death. However, despite substantial evidence indicating the role of tumor-host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the noncellular compartment of the BM microenvironment in patients with AML (n = 10) and age- and sex-matched healthy control subjects (n = 10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We show that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular soluble compartment of AML patient BM. Proteomic analysis revealed that 168 proteins significantly differed in abundance, with 91 upregulated and 77 downregulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (myeloid progenitor inhibitory factor-1) in both AML and myelodysplastic syndrome patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics data set provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource.


Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/patologia , Proteômica/métodos , Estudos de Casos e Controles , Microambiente Celular , Quimiocinas/análise , Quimiocinas CC/metabolismo , Citocinas/análise , Regulação Leucêmica da Expressão Gênica , Humanos , Interleucina-8/metabolismo , Proteínas de Neoplasias/análise
16.
J Neuropathol Exp Neurol ; 79(3): 266-276, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31999342

RESUMO

For amyotrophic lateral sclerosis (ALS), achieving and maintaining effective drug levels in the brain is challenging due to the activity of ATP-binding cassette (ABC) transporters which efflux drugs that affect drug exposure and response in the brain. We investigated the expression and cellular distribution of the ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) using immunohistochemistry in spinal cord (SC), motor cortex, and cerebellum from a large cohort of genetically well characterized ALS patients (n = 25) and controls (n = 14). The ALS group included 17 sporadic (sALS) and 8 familial (fALS) patients. Strong P-gp expression was observed in endothelial cells in both control and ALS specimens. Immunohistochemical analysis showed higher P-gp expression in reactive astroglial cells in both gray (ventral horn) and white matter of the SC, as well as in the motor cortex of all ALS patients, as compared with controls. BCRP expression was higher in glia in the SC and in blood vessels and glia in the motor cortex of ALS patients, as compared with controls. P-gp and BCRP immunoreactivity did not differ between sALS and fALS cases. The upregulation of both ABC transporters in the brain may explain multidrug resistance in ALS patients and has implications for the use of both approved and experimental therapeutics.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Cerebelo/metabolismo , Córtex Motor/metabolismo , Proteínas de Neoplasias/metabolismo , Medula Espinal/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/análise , Adulto , Idoso , Astrócitos/metabolismo , Astrócitos/patologia , Cerebelo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/patologia , Proteínas de Neoplasias/análise , Medula Espinal/patologia
17.
Anal Chim Acta ; 1100: 75-87, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987155

RESUMO

Mass spectrometry imaging (MSI) using the ambient ionization technique enables a direct chemical investigation of biological samples with minimal sample pretreatment. However, detailed morphological information of the sample is often lost due to its limited spatial resolution. In this study, predictive high-resolution molecular imaging was produced by the fusion of ambient ionization MSI with optical microscopy of routine hematoxylin and eosin (H&E) staining. Specifically, desorption electrospray ionization (DESI) and nanospray desorption electrospray ionization (nanoDESI) mass spectrometry were employed to visualize lipid and protein species on mice tissue sections. The resulting molecular distributions obtained by ambient ionization MSI-microscopy fusion were verified with matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MSI and immunohistochemistry (IHC) staining. Label-free molecular imaging with 5-µm spatial resolution can be acquired using DESI and nanoDESI, whereas the typical spatial resolution of ambient ionization MSI was ∼100 µm. In this regard, sharpened molecular histology of tissue sections was achieved, providing complementary references to the pathology. Such a multi-modal integration enables the discovery of potential tumor biomarkers. After image fusion, more than a dozen potential biomarkers on a metastatic mouse lung tissue section and Luminal B breast tumor tissue section were identified.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico por imagem , Lipídeos/análise , Neoplasias Pulmonares/diagnóstico por imagem , Proteínas de Neoplasias/análise , Imagem Óptica , Animais , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos ICR , Espectrometria de Massas por Ionização por Electrospray
18.
J Clin Invest ; 130(2): 958-973, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31961339

RESUMO

Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/biossíntese , Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica , Recombinação Homóloga , Proteínas de Neoplasias/biossíntese , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Tirosina Quinases/biossíntese , Tolerância a Radiação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Dano ao DNA , Feminino , Humanos , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética
19.
Acta Histochem ; 122(2): 151498, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31889532

RESUMO

Dermatofibroma (BFH), atypical fibroxanthoma (AFX) and dermal pleomorphic sarcoma (DPS) are skin-based soft-tissue neoplasms of uncertain lineage. They are classified as "fibrohistiocytic" neoplasms, even if the World Health Organization stated that this term connotes a polymorphic group of lesions that histologically resemble fibroblasts and histiocytes. It is well-known that this group of lesions shows a "fibro-histiocytic-dendritic" and/or a "myofibroblastic" phenotype, even within the same lesion. We studied the expression of cathepsin-k in 34 cases (25 BFH, 5 AFX, 4 DPS) with a broad panel of antibodies. 20 cases (5 dermatofibrosarcoma protuberans, 5 melanomas, 5 basal cell carcinomas, 5 squamous cell carcinomas) were chosen as controls. Although our results need to be validated, they support a myofibroblastic and/or partial myofibroblastic ("proto-myofibroblastic") phenotype and the lineage-plasticity of these neoplasms, highlighting the potential role of cathepsin-k in myofibroblastic trans-differentiation. Cathepsin-k proved to be an additional immunoistochemical marker potentially useful in the diagnostic algorithm.


Assuntos
Carcinoma de Células Escamosas/patologia , Histiocitoma Fibroso Benigno/patologia , Melanoma/patologia , Sarcoma/patologia , Neoplasias Cutâneas/patologia , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/diagnóstico , Diagnóstico Diferencial , Feminino , Histiocitoma Fibroso Benigno/diagnóstico , Humanos , Masculino , Melanoma/diagnóstico , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/metabolismo , Sarcoma/diagnóstico , Pele/patologia , Neoplasias Cutâneas/diagnóstico
20.
Sci Rep ; 10(1): 1154, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980713

RESUMO

Recently our study identified EP3 receptor and galectin-3 as prognosticators of cervical cancer. The aim of the present study was the analysis of EP2 as a novel marker and its association to EP3, galectin-3, clinical pathological parameters and the overall survival rate of cervical cancer patients. Cervical cancer tissues (n = 250), as also used in our previous study, were stained with anti-EP2 antibodies employing a standardized immunohistochemistry protocol. Staining results were analyzed by the IRS scores and evaluated for its association with clinical-pathological parameters. H-test of EP2 percent-score showed significantly different expression in FIGO I-IV stages and tumor stages. Kaplan-Meier survival analyses indicated that EP3-negative/EP2-high staining patients (EP2 IRS score ≥2) had a significantly higher survival rate than the EP3-negative/EP2-low staining cases (p = 0.049). In the subgroup of high galectin-3 expressing patients, the group with high EP2 levels (IRS ≥2) had significantly better survival rates compared to EP2-low expressing group (IRS <2, p = 0.044). We demonstrated that the EP2 receptor is a prognostic factor for the overall survival in the subgroup of negative EP3 and high galectin-3 expressed cervical cancer patients. EP2 in combination with EP3 or galectin-3 might act as prognostic indicators of cervical cancer. EP2, EP3, and galectin-3 could be targeted for clinical diagnosis or endocrine treatment in cervical cancer patients, which demands future investigations.


Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas de Neoplasias/fisiologia , Receptores de Prostaglandina E Subtipo EP2/fisiologia , Neoplasias do Colo do Útero/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Galectina 3/análise , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Estadiamento de Neoplasias , Prognóstico , Isoformas de Proteínas/análise , Receptores de Prostaglandina E Subtipo EP3/deficiência , Receptores de Prostaglandina E Subtipo EP3/genética , Método Simples-Cego , Taxa de Sobrevida , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Adulto Jovem
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