Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 70.657
Filtrar
1.
Lancet Oncol ; 21(9): e431-e443, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888472

RESUMO

Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.


Assuntos
Proteínas de Neoplasias/genética , Tumores Neuroendócrinos/radioterapia , Neoplasias Pancreáticas/radioterapia , Receptores de Formil Peptídeo/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Masculino , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único/genética , Radioisótopos/uso terapêutico , Transcriptoma/efeitos da radiação
2.
Nat Commun ; 11(1): 4660, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938908

RESUMO

Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Histona Desacetilase 1/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Camundongos SCID , Fenilbutiratos/farmacologia , Transdução de Sinais , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Pharm Res ; 37(10): 194, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32918191

RESUMO

PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). RESULTS: MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. CONCLUSION: cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Neoplasias/metabolismo , Farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , 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/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Dibenzocicloeptenos/farmacologia , Dicetopiperazinas/farmacologia , Cães , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Células Madin Darby de Rim Canino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Prazosina/farmacocinética , Quinidina/farmacocinética , Quinolinas/farmacologia , Especificidade por Substrato , Transfecção
4.
Anticancer Res ; 40(10): 5417-5421, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988862

RESUMO

BACKGROUND: Type II diabetes agents have anticancer effects on head and neck squamous cell carcinoma (HNSCC). The mechanistic target of rapamycin (MTOR) pathway represents a putative target. MATERIALS AND METHODS: We interrogated an Affymetrix HNSCC dataset for MTOR-related gene expression. RESULTS: MTOR expression itself was unchanged, but various related genes demonstrated differential expression. Pathway promoters ras homolog (RHEB), MTOR-associated protein (MLST8), and ribosomal protein S6 kinase B1 (RPS6KB1) were up-regulated. Expression of growth suppressors tuberous sclerosis complex 2 (TSC2), programmed cell death 4 (PDCD4), and BCL2 apoptosis regulator-associated agonist of cell death (BAD) were reduced in HNSCC. Upstream, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT serine/threonine kinase 1 (AKT1), and phosphatase and tensin homolog (PTEN) were up-regulated in cancer. CONCLUSION: Several MTOR pathway promoters and tumor suppressors were found to be differentially expressed, favoring MTOR pathway up-regulation in HNSCC. Genomic databases can be interrogated to identify intervention targets and endpoints in HNSCC trials.


Assuntos
Bases de Dados Genéticas , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Neoplasias/genética , Serina-Treonina Quinases TOR/genética , Proteínas Reguladoras de Apoptose/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/patologia , Humanos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas de Ligação a RNA/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína de Morte Celular Associada a bcl/genética , Homólogo LST8 da Proteína Associada a mTOR/genética
5.
Anticancer Res ; 40(10): 5667-5671, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988891

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers. MATERIALS AND METHODS: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database. RESULTS: Our analysis revealed overexpression of DUSP1, DUSP4, PTP4A3, PTPRC and PTPRE genes at all examined stages of RCC. Moreover, we found overexpression of PTPN12 at stage 2, overexpression of CDKN3 at stages 3 and 4, and overexpression of DUSP10 and PTPN22 at stages 2, 3 and 4. Lower expression of DUSP9, PTPR9 and PTPRO was also observed at all stages. CONCLUSION: Significant changes in expression patterns of protein tyrosine phosphatase genes confirm the involvement of this group in crucial carcinogenesis pathways underlying RCC. Thus, we postulate that protein tyrosine phosphatases play an important role in RCC promotion and progression, and may be considered as potential therapeutic targets.


Assuntos
Carcinoma de Células Renais/genética , Proliferação de Células/genética , Oncogenes/genética , Proteínas Tirosina Fosfatases/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Fosfatase 1 de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Antígenos Comuns de Leucócito/genética , Masculino , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genética , Fatores de Risco , Transdução de Sinais/genética , Fumar/efeitos adversos
6.
Anticancer Res ; 40(10): 5883-5893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988919

RESUMO

BACKGROUND/AIM: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. PATIENTS AND METHODS: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). RESULTS: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. CONCLUSION: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Idoso , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Receptor ErbB-2/genética
7.
Ann Hematol ; 99(11): 2629-2637, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980890

RESUMO

Treatment of acute lymphoblastic leukemia (ALL) requires the combination of multiple drugs to integrate a complete remission. The different prognostic factors (age, leukocytes, risk, cytogenetic alterations) allow identifying those patients with a high risk of relapse, but there are few described factors that impact the induction response. The objective was to identify the utility of different risk factors (overexpression of the ABCB1 drug resistance gene, favorable response to steroids (FRS) and early response at day + 8 of treatment) on the percentage of complete remissions and overall survival. This is a prospective, observational study in adult patients with B-ALL without specific cytogenetic alterations, who started induction treatment based on a pretreatment with prednisone and subsequently vincristine (1.6 mg/m2 subcutaneous) plus daunorubicin (45 mg/m2 subcutaneously) on days + 1, + 8, + 15. The ABCB1 resistance gene was evaluated at diagnosis, the FRS at the end of the pretreatment and the early response during day + 8. A total of 53 adult patients diagnosed with ALL Philadelphia negative chromosome (Ph-), with immunophenotype B, with a normal karyotype, were studied. Cases with genetic abnormalities with a poor prognosis were excluded in order to reduce bias. The mean age was 48 years (range 17-68 years). 62.3% of patients were at high risk of relapse. When analyzing the risk factors, 30.2% showed high levels of the ABCB1 resistance gene, without showing an impact on the induction response (OR: 1.218, p = 0.743), but its overexpression was associated with a poor response to steroids as in the absence of early response. Individually, both the FRS (OR: 5.7, p = 0.004) and the absence of early response to day + 8 (OR: 6.42, p = 0.002) showed significance. By combining the different factors, having more than 2 was directly related to a failure (OR: 9.514, p = 0.000). The identification of factors such as FRS such as the persistence of blasts at the end of the first week of treatment is useful to identify patients at risk of failure in induction.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Quimioterapia de Indução , Proteínas de Neoplasias/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Adolescente , Adulto , Idoso , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisolona/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Vincristina/administração & dosagem
8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(7): 759-765, 2020 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879078

RESUMO

OBJECTIVES: To observe the electrophysiological changes of astrocytes in the process of hyperoxia induced apoptosis and analyze the relationship between electrophysiological characteristics and morphological changes. METHODS: Astrocytes were exposed to 90% hyperoxia for 12-72 h. The electrophysiological characteristics of astrocytes in each group were detected by patch clamp technique, and the morphological characteristics of astrocytes were observed at the same time. Then the same batch of astrocytes were collected, and the expression levels of caspase-1, caspase-3, gasdermin D (GSDMD) and gasdermin E (GSDME) were detected by Western blotting. RESULTS: From 12 h to 72 h after hyperoxia exposure, the inward current was significantly lower than that of the control group (P<0.05), while the outward current was significantly decreased at 12 h and increased at 48 h (P<0.05). There was no significant difference between 24 h or 72 h after hyperoxia exposure and the control group (P>0.05). At each time point, the morphology of cells changed correspondingly. Western blotting showed that the expression of caspase-1 was increased significantly at 24 h and decreased significantly at 72 h after hyperoxia exposure (P<0.05); the expression of GSDMD was increased at 12 h and decreased gradually from 24 h to 72 h after hyperoxia exposure (P<0.05); the expression of caspase-3 did not change significantly at 12 h and 24 h after hyperoxia exposure (P>0.05), but began to decrease at 48 h (P<0.05); GSDME increased gradually at 24 h after hyperoxia exposure (P<0.05). CONCLUSIONS: Under hyperoxia exposure, the ion channels of astrocytes are damaged, which can maintain the dysfunction of ion homeostasis, activate GSDME, induce the damaged cells to break away from the apoptotic pathway, and mediate the pyroptosis.


Assuntos
Hiperóxia , Piroptose , Apoptose , Astrócitos , Caspase 1 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Neoplasias , Proteínas de Ligação a Fosfato
9.
Ann Hematol ; 99(11): 2599-2609, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32935190

RESUMO

Methods to estimate bone marrow plasma cells (BMPC) basically include histopathology, cytomorphology, and flow cytometry. The present study compares the outcomes of these methods with special focus on the impact of BMPC-specific characteristics on their recovery by either method. Laboratory reports of diagnostic samples from 238 consecutive patients with suspected or known plasma cell disease were retrospectively analyzed. The median (IQR) proportion of BMPC was 30.0% (15.0-70.0%) by histological review (hBMPC), 7.0% (2.0-16.0%) by smear review (sBMPC), and 3.0% (0.8-10.0%) by flow cytometry (fBMPC). The disparity of results between core biopsy and aspirate smear was enhanced in case of poor quality of the smear, increased BM fiber content, higher grade cell atypia, expression of CD56 (all P < 0.0001), the number of cytogenetic aberrations (P = 0.0002), and abnormalities of the MYC gene (P = 0.0002). Conversely, expression of CD19 and a non-clonal plasma cell phenotype were associated with a lower difference between hBMPC and sBMPC (both P < 0.0001). The disparity between the percentages of sBMPC and fBMPC was associated with the quality of the smear (P = 0.0007) and expression of CD56 (P < 0.0001). Our results suggest that the recovery of BMPC in aspirate specimens not only is a matter of sampling quality but also depends on biological cell properties. Aspiration failure due to malignant type features of BMPC may lead to misclassification of plasma cell disorders and represent a bias for the detection of minimal residual disease after therapy.


Assuntos
Antígenos CD19/biossíntese , Células da Medula Óssea , Antígeno CD56/biossíntese , Mieloma Múltiplo , Proteínas de Neoplasias/biossíntese , Plasmócitos , Adulto , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/classificação , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Neoplasia Residual , Plasmócitos/metabolismo , Plasmócitos/patologia , Estudos Retrospectivos
10.
Ecotoxicol Environ Saf ; 202: 110940, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800223

RESUMO

Recent evidence indicates that chronic, low-dose exposure to mixtures of pesticides can cause adverse responses in a variety of cells, tissues and organs, although interactions between pesticides circulating in the blood and cancer cells remain largely unexplored. The aim of this study was to investigate the potential of a mixture of four pesticides to induce multidrug resistance against the chemotherapeutic agents cisplatin, 5-fluorouracil and temozolomide in the human U87 glioblastoma cell line, and to explore the molecular mechanisms underlying this resistance. We found that the repeated administration of the pesticide mixture (containing the insecticides chlorpyrifos-ethyl and deltamethrin, the fungicide metiram, and the herbicide glyphosate) induced a strong drug resistance in U87 cells. The resistance was durable and transferred to subsequent cell generations. In addition, we detected a significant over-expression of the ATP-binding cassette (ABC) membrane transporters P-gp/ABCB1 and BRCP/ABCG2 as well as a glutathione-S-transferase (GST)/M1-type cellular detoxification function, known to have important roles in multidrug resistance, thus providing molecular support for the acquired multidrug resistance phenotype and shedding light on the mechanism of resistance. We further determined that there was lower mortality in the resistant brain tumor cells and that the mitochondrial apoptosis pathway was activated at a lower rate after chemotherapy compared to non-resistant control cells. In addition, multidrug-resistant cells were found to have both higher motility and wound-healing properties, suggesting a greater metastatic potential. Our results suggest that the investigation of P-gp, BRCP and GST/M1 multidrug resistance gene expression and/or protein levels in biopsy specimens of brain tumor patients who were at risk of pesticide exposure could be beneficial in determining chemotherapy dose and prolonging patient survival.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Praguicidas/toxicidade , Testes de Toxicidade Crônica , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/farmacologia
11.
Vestn Oftalmol ; 136(4): 57-65, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32779457

RESUMO

PURPOSE: To assess the progression of primary open-angle glaucoma (POAG) and to study the role of retinal microcirculation in its progression. MATERIAL AND METHODS: In this 2-year prospective study, the rate of POAG progression was determined using perimetry (ROP1) and spectral domain optical coherence tomography (SD-OCT) by thinning of retinal nerve fiber layer (RNFL) (ROP2) and ganglion cell complex (GCC) (ROP3). The vessel density of parafoveal superficial plexus (VD parafovea) and peripapillary retina (VD ppr) was assessed using OCT angiography, peripheral resistance index (RI), and blood flow velocity in the posterior short ciliary arteries (PSCA) and central retinal artery (CRA) with the use of color Doppler mapping. The predictive properties of each parameter were calculated using the area under receiver operating curve (AUC). RESULTS: Progression was detected in 9.8% cases by perimetry and in 19.7% cases by OCT. The combination of these two methods increased the detection up to 32.8%. Circulatory parameters - VD parafovea (AUC 0.70±0.07), VD ppr (0.715±0.07), PSCA RI (0.801±0.12), CRA RI (0.798±0.11) - had similar high predictive properties as IOP max (0.79±0.05), corneal hysteresis (0.755±0.07), thickness of inner parafoveal layers (0.728±0.07) and RNFL (0.692±0.06). The study revealed the following correlations: ROP1 with maximum IOP (p=0.01), ROP2 with blood flow velocity in PSCA (p=0.01), VD parafovea with corneal hysteresis (p=0.01), and GCC thickness with ocular perfusion pressure (p=0.01). CONCLUSION: The obtained data demonstrates the importance of combining perimetry with OCT for detecting the progression of glaucoma and indicates its relationship with reduced ocular hemoperfusion.


Assuntos
Pressão Intraocular , Doenças do Nervo Óptico , Antígenos de Neoplasias , Proteínas Ligadas por GPI , Humanos , Microcirculação , Proteínas de Neoplasias , Estudos Prospectivos , Retina , Tomografia de Coerência Óptica
12.
PLoS One ; 15(8): e0238466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857809

RESUMO

PURPOSE: Phyllodes tumors (PTs) are biphasic tumors accounting for 0.3-1.5% of all breast tumors. Epithelial membrane proteins (EMPs) have been reported in various malignant tumors but their expression in PTs is unclear. In this study, we aimed to evaluate the expression of EMP1, EMP2, and EMP3 in breast phyllodes tumors (PTs), and to investigate their clinical implications. METHODS: In total, 185 PTs were used for constructing a tissue microarray. Immunohistochemical staining for EMP1, EMP2, and EMP3 was performed, and the results were analyzed along with the clinicopathologic parameters. RESULTS: In total, 185 PTs were included in this study, and comprised 138 benign, 32 borderline, and 15 malignant PTs. In malignant PTs, the epithelial component showed decreased expression of EMP1 (P = 0.027), EMP2 (P = 0.004), and EMP3 (P = 0.032), compared to the benign and borderline PTs. Conversely, stromal component of borderline and malignant PTs showed higher expression of EMP1 (P = 0.027), EMP2 (P = 0.004), and EMP3 (P = 0.032) compared to benign PTs. Expression of EMP1 and EMP3 correlated positively with stromal cellularity and cellular atypia (P < 0.001). In the univariate analysis, stromal EMP3 was associated with shorter disease-free survival (P < 0.001), and shorter overall survival (P = 0.034). CONCLUSION: The expression of EMP1, EMP2, and EMP3 is decreased in the epithelial component and is increased in the stromal component of PT with higher histologic grade. Thus, stromal EMP3 expression may serve as an independent prognostic factor in PT.


Assuntos
Neoplasias da Mama/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Tumor Filoide/metabolismo , Receptores de Superfície Celular/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Tumor Filoide/patologia , Prognóstico , Células Estromais/metabolismo , Células Estromais/patologia , Análise de Sobrevida , Análise Serial de Tecidos
13.
Life Sci ; 259: 118157, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735888

RESUMO

AIMS: Previous studies have demonstrated that circular RNAs play significant roles in several tumors, including lung adenocarcinoma; however, specific biological functions and molecular mechanisms underlying this process remain unclear. MATERIALS AND METHODS: Here, we conducted real-time quantitative PCR (qRT-PCR) to measure hsa_circ_0001588 expression levels in 60 paired lung adenocarcinoma tissues and cell lines. Furthermore, the association between hsa_circ_0001588 and clinical features of lung adenocarcinoma was analyzed. Functional experiments were conducted to assess the influence of hsa_circ_0001588 on proliferation, migration, and invasion in lung adenocarcinoma cells. We detected possible downstream targets of hsa_circ_0001588 using bioinformatics analysis. Luciferase reporter assays, qRT-PCR, and western blotting assays were performed to verify the molecular mechanism underlying hsa_circ_0001588 functions. KEY FINDINGS: We found that hsa_circ_0001588 was prominently upregulated in lung adenocarcinoma tissues and cell lines; elevated expression of hsa_circ_0001588 was positively correlated with poor clinicopathological features of lung adenocarcinoma. Functional experiments revealed that hsa_circ_0001588 acts as an oncogene to promote the proliferation, migration, and invasion of lung adenocarcinoma in vitro. Mechanistically, hsa_circ_0001588 promoted the proliferation, migration, and metastasis of lung adenocarcinoma by binding to miR-524-3p to promote nucleus accumbens-associated protein 1(NACC1) expression. SIGNIFICANCE: Together, our results revealed that hsa_circ_0001588 upregulated the expression of NACC1 by combining with miR-524-3p to promote the proliferation, migration, and invasion of lung adenocarcinoma cells, suggesting that hsa_circ_0001588 may be an underlying therapeutic target for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Circular/genética , RNA Neoplásico/genética , Proteínas Repressoras/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Invasividade Neoplásica/genética , Reação em Cadeia da Polimerase , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Life Sci ; 259: 118168, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32739469

RESUMO

AIMS: Circular RNA PRKCI (circPRKCI) and poly ADP-ribose polymerase 9 (PARP9) are related to the development of cancers. In this study, we aimed to explore the regulatory mechanisms between circPRKCI and PARP9 in EC progression and radioresistance. MATERIALS AND METHODS: The levels of circPRKCI, PARP9 mRNA, and miR-186-5p were assessed by quantitative real time polymerase chain reaction (qRT-PCR). Western blot analysis was employed to examine the levels of several proteins. The viability, colony formation, cell cycle progression, and apoptosis of EC cells were determined with CCK-8, colony formation, or flow cytometry assays. The relationship between circPRKCI or PARP9 and miR-186-5p was verified with the dual-luciferase reporter and RIP assays. KEY FINDINGS: We observed that circPRKCI and PARP9 were upregulated while miR-186-5p was downregulated in EC tissues and cells. Furthermore, circPRKCI knockdown decreased tumor growth in vivo and constrained cell viability, colony formation, cell cycle progression, elevated cell radiosensitivity in EC cells in vitro. Importantly, circPRKCI modulated PARP9 expression through sponging miR-186-5p. Besides, PARP9 overexpression overturned circPRKCI silencing-mediated effects on the viability, colony formation, cell cycle progression, and radiosensitivity of EC cells. SIGNIFICANCE: CircPRKCI regulated cell malignancy and radioresistance through modulating the miR-186-5p /PARP9 axis in EC, which provided a might target for EC treatment.


Assuntos
Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Isoenzimas/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Poli(ADP-Ribose) Polimerases/genética , Proteína Quinase C/genética , RNA Circular/genética , Animais , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Progressão da Doença , Neoplasias Esofágicas/radioterapia , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Células-Tronco Neoplásicas , Interferência de RNA , Radiossensibilizantes/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Ann Hematol ; 99(10): 2343-2349, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32833105

RESUMO

Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Lipase Lipoproteica/deficiência , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Feminino , Genes p53 , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Lipase Lipoproteica/genética , Lipase Lipoproteica/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Modelos de Riscos Proporcionais , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Medição de Risco , Rituximab/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Proteína Supressora de Tumor p53/deficiência , Proteína-Tirosina Quinase ZAP-70/biossíntese , Proteína-Tirosina Quinase ZAP-70/genética
16.
Ann Hematol ; 99(10): 2417-2427, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32862286

RESUMO

For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.


Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/terapia , Proteínas de Neoplasias/genética , Transplante de Células-Tronco de Sangue Periférico , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/química , Terapia Combinada , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Reação em Cadeia da Polimerase/métodos , Prognóstico , Proteínas Proto-Oncogênicas c-abl/genética , Transativadores/biossíntese , Resultado do Tratamento , Proteínas Supressoras de Tumor/biossíntese , Adulto Jovem
17.
DNA Cell Biol ; 39(9): 1621-1638, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32758021

RESUMO

Increasing evidence highlights the clinical significance of stromal cells and immune cells in the liver cancer microenvironment. However, reliable prognostic models have not been well established. This study aimed to develop a gene signature for liver cancer based on stromal and immune scores. Using the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, stromal and immune scores were estimated based on the transcriptome profile of The Cancer Genome Atlas (TCGA) liver cancer cohort. Stromal-/immune-related differentially expressed genes were identified, followed by functional enrichment analysis. The Cox regression model was used to select prognostic genes and construct a gene signature. Its predictive potential was evaluated by receiver operating characteristic (ROC). The correlation between the risk score and immune cell infiltration was analyzed using Tumor Immune Estimation Resource (TIMER). Three hundred sixty-four upregulated and 10 downregulated stromal-/immune-related genes were identified, were mainly enriched in immune-related processes and pathways. Through univariate and multivariate cox survival analysis, a five-gene risk score was constructed, composed of FABP3, HTRA3, OLFML2B, PDZD4 and SLAMF6. Patients with high score indicated a poorer prognosis than those with low risk score. The areas under the ROC curves of overall survival (OS), progression-free interval, 3-, 5-year, OS status were 0.68, 0.57, 0.72, 0.74 and 0.728, indicating its well performance on predicting patients' prognoses. Furthermore, the risk score and the five genes were significantly correlated with immune cell infiltration in the tumor microenvironment. In this study, we proposed a prognostic five-gene signature based on stromal/immune scores in the liver cancer microenvironment.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Hepáticas/genética , Microambiente Tumoral , Idoso , Biomarcadores Tumorais/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Proteína 3 Ligante de Ácido Graxo/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Transcriptoma
18.
Commun Biol ; 3(1): 374, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641750

RESUMO

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Neoplasias da Próstata/epidemiologia , Distribuição por Sexo , Antineoplásicos Hormonais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Betacoronavirus/ultraestrutura , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças , Reposicionamento de Medicamentos , Feminino , Previsões , Hormônios Esteroides Gonadais/fisiologia , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Inibidores de Proteases/uso terapêutico , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Fatores de Risco , Serina Endopeptidases/biossíntese , Serina Endopeptidases/fisiologia , Estados Unidos/epidemiologia , Internalização do Vírus
19.
Medicine (Baltimore) ; 99(29): e21231, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702897

RESUMO

BACKGROUND: The tumor abnormal protein (TAP) test is used to screen for many cancers, but its use for breast cancer has not been studied. METHODS: Tests for carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cancer antigen 15-3 (CA15-3), and TAP were administered to 261 women with operable benign breast disease and 348 with breast cancer. The cutoff value used for TAP was the mean + 3 standard deviations for benign breast disease patients (275.64 µm). Sensitivities and specificities of single biomarker tests and combined tests were compared. The combined tests were defined as positive if any single biomarker was positive, and negative otherwise. RESULTS: The single biomarker test sensitivities were similar: CEA, 7.18%; CA125, 4.89%; CA15-3, 7.47%; and TAP, 4.89%. For the combinations TAP + CEA + CA125, TAP + CEA + CA15-3, TAP + CA125 + CA15-3, and TAP + CEA + CA125 + CA15-3, the sensitivities were 16.67%, 17.82%, 16.38%, and 21.84%, respectively, and the specificities were 93.49%, 97.70%, 93.87%, and 92.72%. CONCLUSIONS: The 4-test combination showed the highest sensitivity (21.84%) and may be auxiliary used in early screening. TAP + CEA + CA15-3 showed high specificity (97.70%) and so could be used for confirming breast cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Antígeno Ca-125/sangue , Antígeno Carcinoembrionário/sangue , Criança , Feminino , Humanos , Pessoa de Meia-Idade , Mucina-1/sangue , Proteínas de Neoplasias/sangue , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Adulto Jovem
20.
PLoS Biol ; 18(7): e3000755, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32644996

RESUMO

Kindlin-1, -2, and -3 directly bind integrin ß cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and links to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human full-length kindlin-3, which reveals a novel homotrimer state. Unlike kindlin-3 monomer, which is the major population in insect and mammalian cell expression systems, kindlin-3 trimer does not bind integrin ß cytoplasmic tail as the integrin-binding pocket in the F3 subdomain of 1 protomer is occluded by the pleckstrin homology (PH) domain of another protomer, suggesting that kindlin-3 is auto-inhibited upon trimer formation. This is also supported by functional assays in which kindlin-3 knockout K562 erythroleukemia cells reconstituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared with those reconstituted with wild-type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation.


Assuntos
Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/química , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Multimerização Proteica , Movimento Celular , Humanos , Integrinas/metabolismo , Células K562 , Proteínas de Membrana/metabolismo , Modelos Moleculares , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Domínios Proteicos , Homologia Estrutural de Proteína , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA