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1.
Adv Anat Pathol ; 30(3): 218-229, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36221225

RESUMO

Over the last years, immune checkpoint inhibitors (ICIs) have demonstrated remarkable anti-tumor activity and beneficial effects in patients with early and advanced melanoma. However, ICIs provide clinical benefit only in a minority of patients due to primary and/or acquired resistance mechanisms. Immunotherapy resistance is a complex phenomenon relying on genetic and epigenetic factors, which ultimately influence the interplay between cancer cells and the tumor microenvironment. Information is accumulating on the cellular and molecular mechanisms underlying the production of resistance and the resulting diminished therapeutic efficacy. In addition, current knowledge on predictors of response and toxicity to immunotherapy and on biomarkers that reliably identify resistant patients is in progress. In this review, we will focus on the tumor microenvironment changes induced by ICIs in melanoma, summarizing the available evidence of clinical trials in the neoadjuvant and metastatic setting. We will also overview the role of potential biomarkers in predicting disease response to ICIs, providing insight into current and future research in this field.


Assuntos
Imunoterapia , Melanoma , Inibidores de Checkpoint Imunológico/farmacologia , Melanoma/patologia , Microambiente Tumoral/efeitos dos fármacos , Biomarcadores/análise , Humanos
2.
Rheumatol Int ; 43(3): 537-543, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36719484

RESUMO

Polyangiitis overlap syndrome is a rare clinical entity comprising patients with overlapping features of more than one vasculitis, usually eosinophilic granulomatosis with polyangiitis (EGPA) and granulomatosis with polyangiitis (GPA). Few cases of polyangiitis overlap syndrome have been described in the literature, mostly associated with c-ANCA, anti-proteinase (PR)-3 positivity, a protean clinical picture characterized by vasculitis, eosinophilia and eosinophilic infiltrates in tissues and a favorable response to steroids and immunosuppressant treatments. Herein, we present a case of a 66-year-old woman with nasal obstruction, external nose deformity, sensorineural hearing loss, peripheral blood eosinophilia, high titer anti-PR3 antibodies and lung involvement. Nasal septum biopsies showed inflammatory infiltrate with eosinophilic component; histopathology of the lung demonstrated necrotizing granulomas associated with inflammatory infiltrate composed of numerous neutrophils and some eosinophils. The patient was diagnosed with polyangiitis overlap syndrome and successfully treated with cyclophosphamide. Recognizing this entity is fundamental given the distinct clinical phenotype and outcomes to therapy in the complex scenario of ANCA-associated vasculitides.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss , Eosinofilia , Granulomatose com Poliangiite , Humanos , Granulomatose com Poliangiite/diagnóstico , Síndrome de Churg-Strauss/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Ciclofosfamida/uso terapêutico , Mieloblastina , Anticorpos Anticitoplasma de Neutrófilos , Eosinofilia/complicações
3.
Int J Mol Sci ; 24(6)2023 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-36983016

RESUMO

In the last decade, cholesterol level has been implicated in several types of cancer, including breast cancer. In the current study, we aimed to investigate the condition of lipid depletion, hypocholesterolemia or hypercholesterolemia reproduced in vitro to analyze the response of different human breast cancer cells. Thus, MCF7 as the luminal A model, MB453 as the HER2 model and MB231 as the triple-negative model were used. No effect on cell growth and viability was detected in MB453 and MB231 cells. In MCF7 cells, hypocholesterolemia (1) reduced cell growth, and Ki67 expression; (2) increased ER/PgR expression; (3) stimulated the 3-Hydroxy-3-Methylglutaryl-CoA reductase and neutral sphingomyelinase and; (4) stimulated the expression of CDKN1A gene coding cyclin-dependent kinase inhibitor 1A protein, GADD45A coding growth arrest and DNA-damage-inducible alpha protein and, PTEN gene coding phosphatase and tensin homolog. All these effects were exacerbated by the lipid-depleted condition and reversed by the hypercholesterolemic condition. The relationship between cholesterol level and sphingomyelin metabolism was demonstrated. In summary, our data suggest that cholesterol levels should be controlled in luminal A breast cancer.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Células MCF-7 , Linhagem Celular Tumoral , Colesterol , Lipídeos
4.
Int J Mol Sci ; 24(24)2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38139092

RESUMO

The role of sphingomyelin metabolism and vitamin C in cancer has been widely described with conflicting results ranging from a total absence of effect to possible preventive and/or protective effects. The aim of this study was to establish the possible involvement of sphingomyelin metabolism in the changes induced by vitamin C in breast cancer cells. The MCF7 cell line reproducing luminal A breast cancer and the MDA-MB-231 cell line reproducing triple-negative breast cancer were used. Cell phenotype was tested by estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 expression, and proliferation index percentage. Sphingomyelin was localized by an EGFP-NT-Lys fluorescent probe. Sphingomyelin metabolism was analyzed by RT-PCR, Western blotting and UFLC-MS/MS. The results showed that a high dose of vitamin C produced reduced cell viability, modulated cell cycle related genes, and changed the cell phenotype with estrogen receptor downregulation in MCF7 cell. In these cells, the catabolism of sphingomyelin was promoted with a large increase in ceramide content. No changes in viability and molecular expression were observed in MB231 cells. In conclusion, a high dose of vitamin C induces changes in the luminal A cell line involving sphingomyelin metabolism.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Células MCF-7 , Neoplasias da Mama/metabolismo , Esfingomielinas , Ácido Ascórbico/farmacologia , Espectrometria de Massas em Tandem , Vitaminas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células
5.
J Biol Chem ; 295(33): 11866-11876, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32616652

RESUMO

Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in ß-amyloid (Aß) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aß oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aß aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aß deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aß oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzopiranos/farmacologia , Encéfalo/efeitos dos fármacos , Agregação Patológica de Proteínas/prevenção & controle , Vitamina E/análogos & derivados , Peptídeos beta-Amiloides/ultraestrutura , Animais , Benzopiranos/farmacocinética , Encéfalo/metabolismo , Encéfalo/patologia , Masculino , Camundongos , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/patologia , Vitamina E/farmacocinética , Vitamina E/farmacologia
6.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922388

RESUMO

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrade tryptophan (Trp) into kynurenine (Kyn) at the initial step of an enzymatic pathway affecting T cell proliferation. IDO1 is highly expressed in various cancer types and associated with poor prognosis. Nevertheless, the serum Kyn/Trp concentration ratio has been suggested as a marker of cancer-associated immune suppression. We measured Kyn and Trp in blood samples of a wide cohort of non-small-cell lung cancer (NSCLC) patients, before they underwent surgery, and analyzed possible correlations of the Kyn/Trp ratio with either IDO1 expression or clinical-pathological parameters. Low Kyn/Trp significantly correlated with low IDO1 expression and never-smoker patients; while high Kyn/Trp was significantly associated with older (≥68 years) patients, advanced tumor stage, and squamous cell carcinoma (Sqcc), rather than the adenocarcinoma (Adc) histotype. Moreover, high Kyn/Trp was associated, among the Adc group, with higher tumor stages (II and III), and, among the Sqcc group, with a high density of tumor-infiltrating lymphocytes. A trend correlating the high Kyn/Trp ratio with the probability of recurrences from NSCLC was also found. In conclusion, high serum Kyn/Trp ratio, associated with clinical and histopathological parameters, may serve as a serum biomarker to optimize risk stratification and therapy of NSCLC patients.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Cinurenina/sangue , Neoplasias Pulmonares/patologia , Triptofano/sangue , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida
7.
J Cell Mol Med ; 24(5): 3053-3063, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32022398

RESUMO

S100B protein bridges chronic mucosal inflammation and colorectal cancer given its ability to activate NF-kappaB transcription via RAGE signalling and sequestrate pro-apoptotic wtp53. Being an S100B inhibitor, pentamidine antagonizes S100B-wtp53 interaction, restoring wtp53-mediated pro-apoptotic control in cancer cells in several types of tumours. The expression of S100B, pro-inflammatory molecules and wtp53 protein was evaluated in human biopsies deriving from controls, ulcerative colitis and colon cancer patients at baseline (a) and (b) following S100B targeting with niosomal PENtamidine VEhiculation (PENVE), to maximize drug permeabilization in the tissue. Cultured biopsies underwent immunoblot, EMSA, ELISA and biochemical assays for S100B and related pro-inflammatory/pro-apoptotic proteins. Exogenous S100B (0.005-5 µmol/L) alone, or in the presence of PENVE (0.005-5 µmol/L), was tested in control biopsies while PENVE (5 µmol/L) was evaluated on control, peritumoral, ulcerative colitis and colon cancer biopsies. Our data show that S100B level progressively increases in control, peritumoral, ulcerative colitis and colon cancer enabling a pro-inflammatory/angiogenic and antiapoptotic environment, featured by iNOS, VEGF and IL-6 up-regulation and wtp53 and Bax inhibition. PENVE inhibited S100B activity, reducing its capability to activate RAGE/phosphor-p38 MAPK/NF-kappaB and favouring its disengagement with wtp53. PENVE blocks S100B activity and rescues wtp53 expression determining pro-apoptotic control in colon cancer, suggesting pentamidine as a potential anticancer drug.


Assuntos
Carcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Pentamidina/administração & dosagem , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Proteína Supressora de Tumor p53/genética , Antígenos de Neoplasias/genética , Biópsia , Carcinoma/genética , Carcinoma/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Lipossomos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/genética , Mucosa/efeitos dos fármacos , NF-kappa B/genética , Microambiente Tumoral/efeitos dos fármacos
8.
Clin Exp Rheumatol ; 38 Suppl 126(4): 180-188, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33025892

RESUMO

OBJECTIVES: To assess whether the use of digital image analysis (DIA) in primary Sjögren's syndrome (pSS) for the calculation of the total area of the salivary gland (SG), focus score (FS) and SG area occupied by the inflammatory infiltrate (area fraction, AF), was able to generate reproducible readings among different raters, reducing disagreement. METHODS: Haematoxylin and Eosin digital slides from pSS and non-specific chronic sialadenitis (NSCS) patients were analysed blindly by 4 independent raters among 3 centres. Using an open-source software (QuPath) raters were asked to provide the total area of the gland i) using a grid-based method and ii) a software-based area-calculation tool, iii) the number of inflammatory foci and iv) the total area of the inflammatory infiltrate. Collected data was used to calculate the inter-rater agreement. RESULTS: For the calculation of the total SG area, DIA generated higher agreement among raters than grid-based calculation (inter-class correlation coefficient ICC=0.85 vs 0.98). Agreement for calculated total area of the inflammatory infiltrate (ICC=0.94) and for AF (ICC=0.94) was higher than infiltrates count number (ICC=0.54) and FS (ICC=0.56). AF achieved a 30% improvement over the FS at generating consensus among raters when used as a diagnostic cut-off. CONCLUSIONS: A digital approach achieved a far superior inter-rater agreement when calculating the total area compared to a grid-based approach. The calculation of AF proved superior to FS in correctly classifying pSS vs NSCS biopsies. We suggest that digitally calculated AF should be used alongside FS for large multi-centre studies to improve data harmonisation.


Assuntos
Síndrome de Sjogren , Algoritmos , Humanos , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Glândulas Salivares/diagnóstico por imagem , Síndrome de Sjogren/diagnóstico
9.
Mol Biol Rep ; 47(9): 6879-6886, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32909215

RESUMO

In recent years, new treatments with novel action mechanisms have been explored for advanced non-small cell lung cancer (NSCLC). Retinoids promote cancer cell differentiation and death and their trafficking and action is mediated from specific cytoplasmic and nuclear receptors, respectively. The purpose of this study was to investigate the effect of Cellular retinol binding protein-1 (CRBP-1) transfection in H460 human NSCLC cell line, normally not expressing CRBP-1. H460 cells were transfected by using a vector pTargeT Mammalian expression system carrying the whole sequence of CRBP-1 gene. For proliferation and apoptosis studies, cells were treated with different concentrations of all-trans Retinoic Acid (atRA) and retinol. AKT-related gene expression was analyzed by using western blot and Signosis array and results analysed by one-way analysis of variance (ANOVA) or by t-student test. CRBP-1+ showed reduced proliferation and viability in basal condition and after atRA treatment when compared to empty-transfected H460 cells. Reduced proliferation in CRBP-1+ H460 cells associated to the down-regulation of pAKT/pERK/pEGFR-related genes. In particular, gene array documented the down-regulation of AKT and Stat-3-related genes, including M-Tor, Akt1, Akt2, Akt3, Foxo1, p27, Jun. Restoration of CRBP-1 expression in H460 cells reduced proliferation and viability in both basal condition and after atRA treatment, likely by down-regulating AKT-related gene level. Further studies are needed to better clarify how those CRBP-1-related intracellular pathways contribute to counteract NSCLC progression in order to suggest a potential tool to improve efficacy of retinoid anti lung cancer adjuvant therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Celulares de Ligação ao Retinol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo , Receptores ErbB/genética , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Celulares de Ligação ao Retinol/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transfecção
10.
Recent Results Cancer Res ; 211: 257-276, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30069773

RESUMO

Epidermal growth factor receptor (EGFR)-mutated (exons 18-21) advanced non-small cell lung cancers (NSCLCs) are generally characterized by exquisite sensitivity to treatment with an EGFR-tyrosine kinase inhibitor (-TKI). First-generation or reversible EGFR-TKIs include gefitinib and erlotinib, while, more recently, second-generation or irreversible EGFR-TKIs have been developed, namely afatinib and dacomitinib, with the aim of overcoming/delaying acquired resistance to treatment. Nevertheless, clinical trials have shown that resistance eventually emerges after a median time of slightly less than one year, regardless of whether first- or second-generation EGFR-TKIs are used. In this context, a secondary EGFR mutation in exon 20, namely T790M, has been found to be responsible for approximately 60% of cases of acquired resistance. Alternatively, T790M resistance mutation can be found de novo, in which case it limits the antitumor activity of both first- or second-generation EGFR-TKIs. Osimertinb is an orally bioavailable, third-generation EGFR-TKI that acts by irreversibly binding both EGFR activating mutations and T790M, while sparing wild-type EGFR. On this basis, osimertinib has proven more efficacious than platinum-based chemotherapy in the setting of EGFR T790M-positive NSCLCs pretreated with a first- or second-generation EGFR-TKI. More recently, in another phase 3 trial, osimertinib outperformed gefitinib or erlotinib as first-line treatment of EGFR-mutated (ex19del or L858R) advanced NSCLCs, thus emerging as a new standard of care in this setting. In the present review, we will discuss the preclinical and clinical development of osimertinib, briefly touching upon its activity in special populations and biomarkers of sensitivity to treatment.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Receptores ErbB/antagonistas & inibidores , Humanos
11.
Gut ; 66(12): 2080-2086, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28893865

RESUMO

OBJECTIVES: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. DESIGN: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. RESULTS: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. CONCLUSION: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.


Assuntos
Doença Celíaca/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Doença Celíaca/diagnóstico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC
12.
Prostate ; 77(2): 196-210, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27696457

RESUMO

BACKGROUND: Glyoxalase 2 (Glo2), together with glyoxalase 1 (Glo1), forms the main scavenging system of methylglyoxal, a potent pro-apoptotic agent mainly generated by glycolysis. An increased rate of glycolysis is a well known signature of cancer cells. As a survival strategy, Glo1 is overexpressed in many human malignant cells, including prostate cancer (PCa), where it plays a crucial role in progression. No information is available on the role of Glo2 in the same ambit. PCa is the most common malignancy affecting men in the western world. Progression to a lethal hormone-refractory PCa represents the major concern in this pathology. Therefore, a deeper understanding of the molecular mechanisms underlying PCa invasiveness and metastasis is urgently needed in order to develop novel therapeutic targets for this incurable state of the malignancy. METHODS: Glo2 and Glo1 expression was examined in clinical samples of PCa by immunohistochemistry and in different PCa cell models by western blotting and quantitative real-time polymerase chain reaction. Gene silencing/overexpression and scavenging/inhibitory agents were used for functional analyses. RESULTS: We demonstrated that Glo2, together with Glo1, represents a novel mechanism in PCa progression as part of a pathway driven by PTEN/PI3K/AKT/mTOR signaling with involvement of PKM2 and ERα. Importantly, Glo1/Glo2 silencing did not alter the behavior of benign cells. CONCLUSIONS: Targeting glyoxalases metabolic pathway may represent a strategy to selectively inhibit advanced PCa. Prostate 77:196-210, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas de Transporte/metabolismo , Receptor alfa de Estrogênio/metabolismo , Lactoilglutationa Liase/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Tioléster Hidrolases/metabolismo , Hormônios Tireóideos/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Transformada , Progressão da Doença , Humanos , Masculino , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Ligação a Hormônio da Tireoide
13.
Mol Carcinog ; 56(9): 2112-2126, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28470764

RESUMO

Glyoxalase 2 (Glo2), a metabolic enzyme, is overexpressed in some human cancers which suggests this enzyme may play a role in human tumorigenesis. In prostate cancer (PCa), the role of Glo2 has been scarcely investigated and there are no studies addressing a causative involvement of this protein in this neoplasia. Here, we examined the immunohistochemical profile of Glo2 in human PCa and benign adjacent tissues and investigated Glo2 involvement in PCa development in human prostate cell lines. PCa and matched adjacent normal tissues were obtained from paraffin sections of primary PCa from 20 patients who had undergone radical prostatectomy. Histopathological diagnosis was confirmed for each sample. Glo2 expression analysis was performed by immunohistochemistry in prostate tissues, and by qRT-PCR and immunoblotting in prostate cell lines. The causative and mechanistic role of Glo2 in prostate tumorigenesis was demonstrated by Glo2 ectopic expression/silencing and employing specific activators/inhibitors. Our results showed that Glo2 was selectively expressed in PCa but not in the luminal compartment of the adjacent benign epithelium consistently in all the examined 20 cases. Glo2 expression in PCa was dependent on androgen receptor (AR) and was aimed at stimulating cell proliferation and eluding apoptosis through a mechanism involving the p53-p21 axis. Glo2 was intensely expressed in the basal cells of benign glands but was not involved in PCa genesis. Our results demonstrate for the first time that Glo2 drives prostate tumorigenesis and suggest that it may represent a novel adjuvant marker in the pathological diagnosis of early PCa.


Assuntos
Carcinogênese , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Tioléster Hidrolases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Silenciamento de Genes , Humanos , Lactoilglutationa Liase/metabolismo , Masculino , Próstata/metabolismo , Transdução de Sinais , Tioléster Hidrolases/genética
14.
BMC Cancer ; 17(1): 502, 2017 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-28747156

RESUMO

BACKGROUND: We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT). METHODS: This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes. RESULTS: Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003). CONCLUSIONS: Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidade , Quimioterapia Adjuvante , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Epirubicina/efeitos adversos , Epirubicina/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Frequência do Gene , Estudos de Associação Genética , Genótipo , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Humanos , Estimativa de Kaplan-Meier , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos
15.
Scand J Gastroenterol ; 52(6-7): 674-677, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28276835

RESUMO

BACKGROUND: Autoimmune gastritis (AIG) is a gastric pathologic condition affecting the mucosa of the fundus and the body and eventually leading to hypo-achlorhydria. AIMS: We report our clinical and pathological experience with AIG. METHODS: Data from patients with a diagnosis of AIG seen in the period January 2002-December 2012 were retrieved. Only patients with complete sets of biopsies were analyzed. RESULTS: Data from 138 patients were available for analysis. Pernicious anemia was present in 25% of patients, iron deficiency anemia was found in 29.7% of patients, hypothyroidism in 23% of patients, type 1 diabetes in 7.9% of patients, and vitiligo in 2.8% of patients. Parietal cell antibodies were positive in 65% of patients, and no patient had serology positive for celiac disease. All gastric biopsies showed glandular atrophy associated with enterochromaffin-like (ECL)-cells hyperplasia, features limited to the mucosa of the fundus and body, and focal glandular intestinal metaplasia. Helicobacter pylori was negative in all cases. CONCLUSIONS: AIG was strongly associated with anemia; atrophy, intestinal metaplasia and ECL hyperplasia in the gastric fundus and body are hallmarks of this condition.


Assuntos
Anemia Ferropriva/epidemiologia , Anemia Perniciosa/epidemiologia , Doenças Autoimunes/complicações , Gastrite/complicações , Helicobacter pylori/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Células Enterocromafins/patologia , Celulas Tipo Enterocromafim/patologia , Feminino , Fundo Gástrico/patologia , Gastrite/patologia , Humanos , Hiperplasia , Hipotireoidismo/epidemiologia , Intestinos/patologia , Itália , Masculino , Metaplasia/patologia , Pessoa de Meia-Idade , Células Parietais Gástricas/imunologia , Estudos Retrospectivos , Vitiligo/epidemiologia , Adulto Jovem
16.
Clin Nephrol ; 2017 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-28737134

RESUMO

Ahead of Print article withdrawn by publisher. The publisher apologizes for any inconvenience this has caused. The article was scheduled for the journal "Clinical Nephrology. Case Studies" (issn 2196-5293). The article is available in PubmedCentral: https://www.ncbi.nlm.nih.gov/pubmed/29350220 
.

17.
Mediators Inflamm ; 2017: 8102170, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29375200

RESUMO

Prevalence of thyroid dysfunction and its impact on cognition in older people has been demonstrated, but many points remain unclarified. In order to study the effect of aging on the thyroid gland, we compared the thyroid gland of very old mice with that of younger ones. We have first investigated the changes of thyroid microstructure and the possibility that molecules involved in thyroid function might be associated with structural changes. Results from this study indicate changes in the height of the thyrocytes and in the amplitude of interfollicular spaces, anomalous expression/localization of thyrotropin, thyrotropin receptor, and thyroglobulin aging. Thyrotropin and thyrotropin receptor are upregulated and are distributed inside the colloid while thyroglobulin fills the interfollicular spaces. In an approach aimed at defining the behavior of molecules that change in different physiopathological conditions of thyroid, such as galectin-3 and sphingomyelinase, we then wondered what was their behavior in the thyroid gland in aging. Importantly, in comparison with the thyroid of young animals, we have found a higher expression of galectin-3 and a delocalization of neutral sphingomyelinase in the thyroid of old animals. A possible relationship between galectin-3, neutral sphingomyelinase, and aging has been discussed.


Assuntos
Envelhecimento/patologia , Galectina 3/fisiologia , Esfingomielina Fosfodiesterase/fisiologia , Glândula Tireoide/patologia , Animais , Galectina 3/análise , Masculino , Camundongos , Receptores da Tireotropina/análise , Esfingomielina Fosfodiesterase/análise , Tireotropina/análise
18.
J Cell Sci ; 127(Pt 8): 1699-711, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24554430

RESUMO

Embryonal rhabdomyosarcomas (ERMSs) show elevated levels of PAX7, a transcription factor that marks quiescent adult muscle stem (satellite) cells and is important for proliferation and survival of activated satellite cells and whose timely repression is required for myogenic differentiation. However, the mechanism of PAX7 accumulation in ERMSs and whether high PAX7 causes uncontrolled proliferation in ERMS remains to be elucidated. The receptor for advanced glycation end-products (RAGE, encoded by AGER) transduces a myogenic and anti-proliferative signal in myoblasts, and stable transfection of the ERMS cell line TE671, which does not express RAGE, with AGER results in reduced proliferation and formation of tumor masses in vivo, and enhanced apoptosis and myogenic differentiation. Herein, we show that RAGE expression is low or absent in human ERMSs. We also show that in ERMS cells (1) PAX7 accumulates owing to absent or low RAGE signaling; (2) elevated PAX7 levels reduce RAGE expression and levels of MyoD and myogenin, muscle-specific transcription factors required for myoblast proliferation arrest and differentiation, respectively; (3) PAX7 supports myoblast proliferation by reducing the levels of MyoD, primarily by promoting its degradation; and (4), when ectopically expressed in ERMS cells, that RAGE upregulates myogenin which upregulates MyoD and downregulates PAX7, with consequent inhibition of proliferation and stimulation of differentiation. Thus, failure to express RAGE and, hence, MyoD and myogenin above a critical level in ERMS cells might result in deregulated PAX7 expression leading to uncontrolled proliferation and, potentially, to rhabdomyosarcomagenesis.


Assuntos
Proliferação de Células , Fator de Transcrição PAX7/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Rabdomiossarcoma Embrionário/metabolismo , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Proteína MyoD/metabolismo , Mioblastos/metabolismo , Miogenina/metabolismo , Rabdomiossarcoma Embrionário/patologia , Transdução de Sinais , Regulação para Cima
19.
Mediators Inflamm ; 2016: 3937057, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27194825

RESUMO

Today a large number of studies are focused on clarifying the complexity and diversity of the pathogenetic mechanisms inducing Parkinson disease. We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces Parkinson disease, to evaluate the change of midbrain structure and the behavior of the anti-inflammatory factor e-cadherin, interleukin-6, tyrosine hydroxylase, phosphatase and tensin homolog, and caveolin-1. The results showed a strong expression of e-cadherin, variation of length and thickness of the heavy neurofilaments, increase of interleukin-6, and reduction of tyrosine hydroxylase known to be expression of dopamine cell loss, reduction of phosphatase and tensin homolog described to impair responses to dopamine, and reduction of caveolin-1 known to be expression of epithelial-mesenchymal transition and fibrosis. The possibility that the overexpression of the e-cadherin might be implicated in the anti-inflammatory reaction to MPTP treatment by influencing the behavior of the other analyzed molecules is discussed.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Caderinas/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Animais , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Tirosina 3-Mono-Oxigenase/metabolismo
20.
Carcinogenesis ; 36(9): 1071-83, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26153023

RESUMO

Rhabdomyosarcoma represents about 50% of soft-tissue sarcomas and 10% of malignant solid tumors in childhood. Embryonal rhabdomyosarcoma (ERMS) is the most frequent subtype, suggested to have an origin in muscle precursor cells that fail to exit the cell cycle and terminally differentiate mainly because of overexpression of the transcription factor, PAX7, which sustains proliferation, migration and invasiveness in ERMS cells. Artesunate (ARS) is a semi-synthetic derivative of artemisinin (ART), a natural compound well known as an antimalarial drug. However, ART and its derivatives have been found efficacious even as anticancer drugs that induce cell cycle arrest and/or apoptosis in several kinds of cancer. Here, we show that ARS dose-dependently induces DNA damage and apoptosis in ERMS cell lines. Production of reactive oxygen species (ROS) and activation of p38 MAPK have a central role in triggering ARS-mediated apoptosis in ERMS cells; indeed either the antioxidant, N-acetylcysteine or the p38 MAPK inhibitor, SB203580, protects ERMS cells from ARS-induced apoptosis. Moreover, ARS treatment in ERMS cells ROS-dependently induces the expression of the myo-miRs, miR-133a and miR-206, which are down-regulated in RMS, and reduces PAX7 protein levels. Finally, ARS upregulates the expression of the adhesion molecules, NCAM and integrin ß1, and reduces migration and invasiveness of ERMS cells in vitro, and ARS treatment reduces of about 50% the growth of ERMS xenografts in vivo. Our results are the first evidence of efficacy of ART derivatives in restraining ERMS growth in vivo, and suggest ARS as a potential candidate for therapeutic treatment of ERMS.


Assuntos
Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rabdomiossarcoma Embrionário/tratamento farmacológico , Rabdomiossarcoma Embrionário/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Acetilcisteína/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/fisiologia , Artemisininas/uso terapêutico , Artesunato , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Dano ao DNA/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Integrina beta1/biossíntese , Camundongos , MicroRNAs/biossíntese , Invasividade Neoplásica , Transplante de Neoplasias , Moléculas de Adesão de Célula Nervosa/biossíntese , Fator de Transcrição PAX7/biossíntese , Piridinas/farmacologia , Transplante Heterólogo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
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