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The effect of anti-algics on tumor progression and the overall survival of patients is controversial and remains unclear. Herein, we disclose the in vitro effects of the local anesthetics lidocaine, ropivacaine, and levobupivacaine on breast (MCF7), prostate (PC3, LNCaP), and bladder (TCCSUP, HT1376) cancer cell lines, both as monotherapy and in combination with standard-of-care therapeutics. Assays for cell proliferation, viability, death profile, and migration were performed. Additionally, we explored the clinical outcomes of opioid use through a cross-sectional study involving 200 metastatic prostate cancer patients. The main clinical data collected included the type of opioid therapy administered, dosage, treatment duration, disease progression, and overall survival. Results obtained demonstrate that treatment with local anesthetics has a promising selective anti-tumor effect on these types of cancer, with higher effects when associated with docetaxel. This points out the use of local anesthetics as an added value in the treatment of prostate carcinoma patients. Alternatively, chronic opioid use was correlated with reduced overall survival (p < 0.05) and progression-free survival (p < 0.05) at each treatment line in the observational study. While these results provide valuable insights, larger prospective studies are imperative to comprehensively evaluate the clinical impact of opioid analgesics in prostate cancer patients.
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Transtornos Relacionados ao Uso de Opioides , Neoplasias da Próstata , Neoplasias Urológicas , Humanos , Masculino , Analgésicos Opioides , Anestésicos Locais/farmacologia , Anestésicos Locais/uso terapêutico , Estudos Transversais , Estudos Prospectivos , Neoplasias da Próstata/tratamento farmacológico , FemininoRESUMO
Cell-based assays, conducted on monolayer (2D) cultured cells, are an unquestionably valuable tool for biomedical research. However, three-dimensional (3D) cell culture models have gained relevance over the last few years due to the advantages of better mimicking the microenvironment and tissue microarchitecture in vivo. Recent magnetic-based 3D (m3D) cell culture systems can be used for this purpose. These systems are based on exposing magnetized cells to magnetic fields by levitation, bioprinting, or ring formation to promote cell aggregation into 3D structures. However, the successful development of these structures is dependent on several methodological characteristics and can be applied to mimic different human tissues. Thus, a systematic review was performed using Medline (via Pubmed), Scopus, and Web of Science (until February 2022) databases to aggregate studies using m3D culture in which human tissues were mimicked. The search generated 3784 records, of which 25 met the inclusion criteria. The usability of these m3D systems for the development of homotypic or heterotypic spheroids with or without scaffolds was explored in these studies. We also explore methodological differences specifically related to the magnetic method. Generally, the development of m3D cultures has been increasing, with bioprinting and levitation systems being the most used to generate homotypic or heterotypic cultures, mainly to mimic the physiology of human tissues, but also to perform therapeutic screening. This systematic review showed that there are areas of research where the application of this method remains barely explored, such as cancer research.
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Bioimpressão , Esferoides Celulares , Humanos , Técnicas de Cultura de Células em Três Dimensões , Técnicas de Cultura de Células/métodos , Campos Magnéticos , Engenharia TecidualRESUMO
Breast cancer (BC) is one of the most common types of cancer and the second leading cause of death in women. Local anaesthetics (LAs) and opioids have been shown to influence cancer progression and metastasis formation in several pre-clinical studies. However, their effects do not seem to promote consensus. A systematic review was conducted using the databases Medline (via PubMed), Scopus, and Web of Science (2010 to December 2021). Search terms included "lidocaine", "ropivacaine", "levobupivacaine", "morphine", "methadone", "breast cancer", "breast carcinoma" and "breast neoplasms" in diverse combinations. The search yielded a total of 784 abstracts for initial review, 23 of which met the inclusion criteria. Here we summarise recent studies on the effect of analgesics and LAs on BC cell lines and animal models and in combination with other treatment regimens. The results suggest that local anaesthetics have anti-tumorigenic properties, hence their clinical application holds therapeutic potential. Regarding morphine, the findings are conflicting, but this opioid appears to be a tumour-promoting agent. Methadone-related results are scarce. Additional research is clearly required to further study the mechanisms underlying the controversial effects of each analgesic or LA to establish the implications upon the outcome and prognosis of BC patients' treatment.
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Anestésicos Locais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Morfina/efeitos adversos , Anestésicos Locais/farmacologia , Animais , Neoplasias da Mama/induzido quimicamente , Linhagem Celular Tumoral , Feminino , Humanos , Levobupivacaína/farmacologia , Levobupivacaína/uso terapêutico , Lidocaína/farmacologia , Lidocaína/uso terapêutico , Ropivacaina/farmacologia , Ropivacaina/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Bladder cancer (BC) is the most common cancer of the urinary tract and despite all innovations, remains a major challenge due to high morbidity and mortality. Genomic and epigenetic analyses allowed the discovery of new genes and pathways involved in the pathogenesis and regulation of BC. However, the effect on mortality has been modest and the development of new targets for BC treatment are needed. Recent evidence suggests that cancer cells are under increased stress associated with oncogenic transformation, with changes in metabolic activity and increased generation of reactive oxygen species (ROS). The increased amounts of ROS in cancer cells are associated with stimulation of cellular proliferation, promotion of mutations and genetic instability, as well as alterations in cellular sensitivity to anticancer agents. Since these mechanisms occur in cancer cells, there is a close link between oxidative stress (OS) and BC with implications in prevention, carcinogenesis, prognosis, and treatment. We address the role of OS as an enemy towards BC development, as well as an ally to fight against BC. This review promises to expand our treatment options for BC with OS-based therapies and launches this approach as an opportunity to improve our ability to select patients most likely to respond to personalized therapy.
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Estresse Oxidativo , Neoplasias da Bexiga Urinária/patologia , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Modelos Biológicos , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
AIM: To investigate the association between root canal treatment outcome, diabetes mellitus, and alterations of the angiogenic process. METHODOLOGY: A retrospective observational study was conducted in healthy (control group, CG) and diabetic (type II diabetes mellitus group, DG) patients after root canal treatment. The follow-up appointments were performed to clinically and radiographically observe symptoms, the healing of periapical lesions and the quality of root fillings. In the animal model study, diabetic Goto-Kakizaki (GK) rats and control Wistar rats were used. After 21 days of pulp exposure and the development of apical periodontitis (AP), the mandibles were removed for scintigraphic, radiographic, histopathological and molecular analyses. Chi-square tests were performed to examine the variables related to endodontic outcome and differences between animal groups were assessed using the Student's t-test. RESULTS: The group of patients with diabetes had a significantly lower rate of success following root canal treatment than the CG (p < .001). Logistic regression suggested that diabetes is a risk factor for success of root canal treatment. In the animal study, GK rats had significantly higher fasting glycaemia at t0 and t21 (p < .001) and triglycerides levels (p < .05) and area under the curve (AUC) during the insulin tolerance test at t21 (p < .001). AP area was significantly greater in GK rats (p < .05). Histologically, diabetic rats had increased signs of periodontal ligament inflammation 21 days after the induction of apical periodontitis, with fibro-hyaline matrix filling and vessel with undefined walls. Wistar rats had significantly increased vascular endothelial growth factor (VEGF) levels and VEGF/Ang-2 ratio 21 days after AP induction (p < .08; p < .07). GK rats had intrinsically lower levels of VEGF than control rats (p < .05), which did not change after AP. CONCLUSION: Diabetes mellitus should be considered as an important factor in the prognosis of root canal treatment and its outcomes over time. Future strategies to improve angiogenesis and tissue repair should be pursued to achieve better root canal treatment outcomes in diabetic patients.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Periodontite Periapical , Animais , Cavidade Pulpar , Diabetes Mellitus Experimental/complicações , Humanos , Periodontite Periapical/terapia , Ratos , Ratos Wistar , Tratamento do Canal Radicular , Fator A de Crescimento do Endotélio VascularRESUMO
The aim of this study was to evaluate the cytotoxic effects of an enzymatic mouthwash and of a chlorhexidine mouthwash on human gingival fibroblasts. The metabolic activity of the fibroblasts exposed to each mouthwash was assessed by the MTT assay and the protein content was assessed by the SRB assay. The flow cytometry was used to evaluate the cell cycle and the types of cell death. The oxidative status was evaluated through the DCF and the DHE probes and the intracellular GSH concentration and the mitochondrial membrane potential through JC-1. The cytotoxicity of both mouthwashes was found to be dependent on the exposure time and on the concentration. However, the cytotoxicity of the enzymatic mouthwash was found to be lower than that of the chlorhexidine mouthwash. A trend towards increased oxidative stress was observed for both mouthwashes. After exposing the fibroblasts to the mouthwashes, a G2/M phase block was observed and cell death occurred predominantly by necrosis. The effects of chlorhexidine on fibroblasts were identified at lower concentrations than those used in clinical practice. Therefore, the use of chlorhexidine as an antiseptic in surgical and postoperative situations should be limited. In order to clarify the clinical significance of the enzymatic mouthwash cytotoxicity new clinical studies will be necessary.
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Anti-Infecciosos Locais , Placa Dentária , Clorexidina , Fibroblastos , Humanos , Antissépticos BucaisRESUMO
Acute pancreatitis (AP) is a severe inflammation of the pancreas presented with sudden onset and severe abdominal pain with a high morbidity and mortality rate, if accompanied by severe local and systemic complications. Numerous studies have been published about the pathogenesis of AP; however, the precise mechanism behind this pathology remains unclear. Extensive research conducted over the last decades has demonstrated that the first 24 h after symptom onset are critical for the identification of patients who are at risk of developing complications or death. The identification of these subgroups of patients is crucial in order to start an aggressive approach to prevent mortality. In this sense and to avoid unnecessary overtreatment, thereby reducing the financial implications, the proper identification of mild disease is also important and necessary. A large number of multifactorial scoring systems and biochemical markers are described to predict the severity. Despite recent progress in understanding the pathophysiology of AP, more research is needed to enable a faster and more accurate prediction of severe AP. This review provides an overview of the available multifactorial scoring systems and biochemical markers for predicting severe AP with a special focus on their advantages and limitations.
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Biomarcadores/sangue , Pancreatite/diagnóstico , Doença Aguda , Humanos , Interleucinas/sangue , Doenças Metabólicas/complicações , Doenças Metabólicas/patologia , Pancreatite/diagnóstico por imagem , Pancreatite/metabolismo , Prognóstico , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Fator de Necrose Tumoral alfa/sangueRESUMO
Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that, when classified as severe, is associated with high morbidity and mortality. Promptly identifying the severity of AP is of extreme importance for improving clinical outcomes. The aim of this study was to compare the prognostic value of serological biomarkers, ratios, and multifactorial scores in patients with acute biliary pancreatitis and to identify the best predictors. In this observational and prospective study, the biomarkers, ratios and multifactorial scores were evaluated on admission and at 48 h of the symptom onset. On admission, regarding the AP severity, the white blood count (WBC) and neutrophil-lymphocyte ratio (NLR), and regarding the mortality, the WBC and the modified Marshall score (MMS) showed the best predictive values. At 48 h, regarding the AP severity, the hepcidin, NLR, systemic inflammatory response index (SIRI) and MMS and regarding the mortality, the NLR, hepcidin and the bedside index for severity in AP (BISAP) score, showed the best predictive values. The present study enabled the identification, for the first time, of SIRI as a new prognostic tool for AP severity, and validated hepcidin and the NLR as better prognostic markers than C-reactive protein (CRP) at 48 h of symptom onset.
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Biomarcadores/sangue , Hepcidinas/sangue , Pancreatite/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pancreatite/mortalidade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To compare the treatments used to treat dentin hypersensitivity (DH), based on its efficacy and effect duration. METHODS: Medline/PubMed, Cochrane Library, EMBASE and ClinicalTrials were searched for articles published between 1 January 2008 and 14 November 2018, in English, Portuguese or Spanish, reporting clinical trials, completed and with results. This systematic review protocol was registered in PROSPERO, number CRD42019121986. RESULTS: Seventy-four randomised clinical trials were included in the systematic review, reporting patients from 16 to 65 years old, with a clinical diagnosis of DH, that evaluate the efficacy of a desensitising product, compared to pre-treatment, used the evaporative method stimulation and the visual analogue scale. These studies evaluated 5366 patients and at least 9167 teeth. Seven follow-up periods were considered corresponding to an immediate, medium or long-time effect. Sixty-six studies were included in the quantitative synthesis. Glutaraldehyde with HEMA, glass ionomer cements and Laser present significant immediate (until 7 days) DH reduction. Medium-term (until 1 month) reduction was observed in stannous fluoride, glutaraldehyde with HEMA, hydroxyapatite, glass ionomer cements and Laser groups. Finally, long-term significant reduction was seen at potassium nitrate, arginine, glutaraldehyde with HEMA, hydroxyapatite, adhesive systems, glass ionomer cements and LASER. CONCLUSIONS: All active ingredients show efficacy in DH reduction in different follow-up times. Only in-office treatments are effective in immediate DH reduction, maintaining its efficacy over time. For long-time effects, at-home treatments can also be used. More standardised evaluation protocols should be implemented to increase the robustly of the results.
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Dessensibilizantes Dentinários , Sensibilidade da Dentina , Adolescente , Adulto , Idoso , Dentina , Seguimentos , Cimentos de Ionômeros de Vidro , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Acute pancreatitis (AP) is a severe disease associated with high morbidity and mortality. Clinical studies can provide some data concerning the etiology, pathophysiology, and outcomes of this disease. However, the study of early events and new targeted therapies cannot be performed on humans due to ethical reasons. Experimental murine models can be used in the understanding of the pancreatic inflammation, because they are able to closely mimic the main features of human AP, namely their histologic glandular changes and distant organ failure. These models continue to be important research tools for the reproduction of the etiological, environmental, and genetic factors associated with the pathogenesis of this inflammatory pathology and the exploration of novel therapeutic options. This review provides an overview of several murine models of AP. Furthermore, special focus is made on the most frequently carried out models, the protocols used, and their advantages and limitations. Finally, examples are provided of the use of these models to improve knowledge of the mechanisms involved in the pathogenesis, identify new biomarkers of severity, and develop new targeted therapies.
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Modelos Animais de Doenças , Pancreatite Necrosante Aguda/etiologia , Animais , Biomarcadores/metabolismo , Camundongos , Pancreatite Necrosante Aguda/metabolismo , Pancreatite Necrosante Aguda/patologia , RatosRESUMO
Colorectal cancer (CRC) is the second most frequent and fatal cancer in Western countries. Understanding its biology with different incidence along the colon and rectum, genetic profile and how these factors contribute to local/distant progression, has been hampered by the lack of a suitable CRC model. We report a reproducible model, using human CRC cell lines (CL) (WiDr, LS1034, C2BBe1) injected (1â¯×â¯107 cells/animal) in RNU rats (nâ¯=â¯55) which underwent cecostomy and descending colostomy with mucosal-cutaneous fistula of the sigmoid colon. CL were characterized by immunohistochemistry: CK20, CDX2, P53, vimentin, Ki67, CD44, CD133, E-cadherin, ß-catenin and CEA; cancer stem cells-immune system interaction was studied and tumor progression was assessed with nuclear medicine imaging (99mTc-MIBI). Animals developed locally invasive tumors and with WiDr neural invasion was registered. Cancer stem cells were detected in WiDr (CD44 positive). All the cell lines stimulated the immune system, being WiDr the most aggressive. Imaging studies demonstrated tumor uptake. With this CRC model we can study the microenvironment role and tumor-stroma interactions. All CL developed primary disease, but only the WiDR established neural invasion which may represent a metastatic pathway. This model can help unveiling the underlying metastatic mechanisms, and ultimately test better therapeutic approaches for CRC.
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OBJECTIVE: Our aim was to evaluate the effects of glucose levels and diabetes mellitus in prostate cancer (PCa) biology. MATERIALS AND METHODS: Two PCa cell lines (LNCap and PC3) were cultured in RPMI medium with different glucose concentrations [5mM (LG) and 25mM (HG)]. Expressions of androgen receptor, Her2/neu and glucose transporters (GLUT1, 3, 5 and 12) were evaluated by flow cytometry. Proliferation rate was assessed by colorimetric assay MTT and cellular characterization was performed by haematoxylin and eosin staining. Additionally, we performed a cross sectional analysis of 704 patients undergoing radical prostatectomy who were divided into two groups (diabetic and non-diabetic). An analysis of clinical and histological data seeking to identify the differences on tumor aggressiveness between the two groups was performed. RESULTS: In LNCaP cell line, when the glucose concentration in the medium increased, there was an increased in AR expression. Regarding expression of Her2/neu receptor, medium's glucose concentration significantly changed the expression of this receptor in both PC3 and LNCaP cell lines. Growth rate was higher on the HG medium for both cell lines. The clinical study of patients undergoing radical prostatectomy revealed no relationship between the presence of diabetes and the development of more aggressive tumours. Diabetic patients had significantly higher prostatic volumes, however, no significant difference was found between the relapse risk classification or the ISUP classification between the two groups. CONCLUSIONS: Our results showed that medium glucose concentration could influence prostate cancer cells growing but not the aggressiveness.
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Glicemia/metabolismo , Diabetes Mellitus/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Estudos Transversais , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Células PC-3 , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Receptor ErbB-2/metabolismoRESUMO
Immune surveillance seems to represent an effective tumor suppressor mechanism. However, some cancer cells survive and become variants, being poorly immunogenic and able to enter a steady-state phase. These cells become functionally dormant or remain hidden clinically throughout. Neoplastic cells seem to be able to instruct immune cells to undergo changes promoting malignancy. Radiotherapy may act as a trigger of the immune response. After radiotherapy a sequence of reactions occurs, starting in the damage of oncogenic cells by multiple mechanisms, leading to the immune system positive feedback against the tumor. The link between radiotherapy and the immune system is evident. T cells, macrophages, Natural Killer cells and other immune cells seem to have a key role in controlling the tumor. T cells may be dysfunctional and remain in a state of T cell exhaustion, nonetheless, they often retain a high potential for successful defense against cancer, being able to be mobilized to become highly functional. The lack of clinical trials on a large scale makes data a little robust, in spite of promising information, there are still many variables in the studies relating to radiation and immune system. The clarification of the mechanisms underlying immune response to radiation exposure may contribute to treatment improvement, gain of life quality and span of patients.
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Sistema Imunitário/fisiologia , Neoplasias/radioterapia , Evasão Tumoral , Humanos , Tolerância Imunológica , Neoplasias/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Endometrial cancer is the most frequent gynecological malignancy in developed world. Cancer stem cells (CSC) are recognized as a small proportion of cells among the tumor cell population that are capable of self-renewal, aberrant differentiation, and escape homeostasis. This review aims to systematize the existing evidence of CSC of endometrial cancer and its clinical translation. In endometrial cancer, the cancer stem cell hypothesis has been studied in vitro using the isolation of colony forming units, side population with dye efflux capacity, and tumorospheres. The stem cell markers for endometrial cancer do not have uniform characteristics, albeit CD133 and aldehyde dehydrogenase (ALDH) were being associated with CSC phenotype. The application of endometrial CSC on xenograft models proves the tumorigenic capacity of this small group of cells. The metastatic process has been explained due to epithelial-mesenchymal transition (EMT) in which CSC seems to have a critical role. The chemoresistance is characteristic of CSC that in endometrial cancer has been shown in CSC phenotype and associated with CSC markers. The most ambitious potential for CSC is the development of targeted therapies. Its application on endometrial cancer is still poor, being a future perspective for research.
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Neoplasias do Endométrio/patologia , Transição Epitelial-Mesenquimal/fisiologia , Células-Tronco Neoplásicas/patologia , Animais , Feminino , HumanosRESUMO
Retinoblastoma is a tumor that mainly affects children under 5 years, all over the world. The origin of these tumors is related with mutations in the RB1 gene, which may result from genetic alterations in cells of the germ line or in retinal somatic cells. In developing countries, the number of retinoblastoma-related deaths is higher due to less access to treatment, unlike what happens in developed countries where survival rates are higher. However, treatments such as chemotherapy and radiotherapy, although quite effective in treating this type of cancer, do not avoid high indices of mortality due to secondary malignances which are quite frequent in these patients. Additionally, treatments such as cryotherapy, thermotherapy, thermochemotherapy, or brachytherapy represent other options for retinoblastoma. When all these approaches fail, enucleation is the last option. Photodynamic therapy might be considered as an alternative, particularly because of its non-mutagenic character. Photodynamic therapy is a treatment modality based on the administration of photosensitizing molecules that only upon irradiation of the tumor with a light source of appropriate wavelength are activated, triggering its antitumor action. This activity may be not only due to direct damage to tumor cells but also due to damage caused to the blood vessels responsible for the vascular supply of the tumor. Over the past decades, several in vitro and in vivo studies were conducted to assess the effectiveness of photodynamic therapy in the treatment of retinoblastoma, and very promising results were achieved.
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Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Retinoblastoma/terapia , Pré-Escolar , Humanos , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Proteína do Retinoblastoma/genéticaRESUMO
Diffuse large B cell lymphoma is recognized as a heterogeneous group of hematological malignancies; two main subtypes germinal center B and activated B cells are well defined although 15% of patients remain with unclassifiable disease. R-CHOP treatment has proven to provide very effective results in limited or advanced stage of the disease. However, treatment solely involving R-CHOP submits the patient to possible chemotherapy-induced toxicities, which may be avoided with the use of radiotherapy. Patients with early stage localized disease or who are particularly unresponsive to chemotherapy may be more suitable for mixed modality treatment with R-CHOP and consolidative radiotherapy. Although radiotherapy is being slowly phased out by other treatment strategies including chemotherapy and therapeutic drugs, it is still a highly important method of treatment. The different forms of radiotherapy can be used alongside these "new-age" treatment strategies to further improve prognostic outcomes and overall survival rates. The establishment of radiotherapy as a treatment strategy provides a highly beneficial prognostic advantage in early stage, localized disease.
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Quimiorradioterapia/métodos , Linfoma Difuso de Grandes Células B/radioterapia , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona , Rituximab , VincristinaRESUMO
Hepatocellular carcinoma (HCC) is the most common primary liver tumor (PLT), with cholangiocarcinoma (CC) being the second most frequent. Glucose transporter 1 (GLUT-1) expression is increased in PLTs and therefore it is suggested as a therapeutic target. Flavonoids, like quercetin, are GLUT-1 competitive inhibitors and may be considered as potential therapeutic agents for PLTs. The objective of this study was evaluation of quercetin anticancer activity in three human HCC cell lines (HepG2, HuH7, and Hep3B2.1-7) and in a human CC cell line (TFK-1). The possible synergistic effect between quercetin and sorafenib, a nonspecific multikinase inhibitor used in clinical practice in patients with advanced HCC, was also evaluated. It was found that in all the cell lines, quercetin induced inhibition of the metabolic activity and cell death by apoptosis, followed by increase in BAX/BCL-2 ratio. Treatment with quercetin caused DNA damage in HepG2, Hep3B2.1-7, and TFK-1 cell lines. The effect of quercetin appears to be independent of P53. Incubation with quercetin induced an increase in GLUT-1 membrane expression and a consequent reduction in the cytoplasmic fraction, observed as a decrease in (18)F-FDG uptake, indicating a GLUT-1 competitive inhibition. The occurrence of synergy when sorafenib and quercetin were added simultaneously to HCC cell lines was noticed. Thus, the use of quercetin seems to be a promising approach for PLTs through GLUT-1 competitive inhibition.
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Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quercetina/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fluordesoxiglucose F18/farmacocinética , Transportador de Glucose Tipo 1/metabolismo , Células Hep G2/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quercetina/administração & dosagem , Sorafenibe , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Liver, the largest intern organ of the human body, is responsible for several vital tasks such as digestive and excretory functions, as well as for nutrients storage and metabolic functions, synthesis of new molecules and purification of toxic chemicals. Cirrhosis, fibrosis and hepatocellular carcinoma are the most prevalent liver diseases. Despite all the studies performed so far, treatment options for these diseases are very limited. For this reason, it is urgent to find effective therapies for these pathologies. Several studies have been performed during the last decade about the possible application of human amniotic membrane in hepatic diseases therapy. Promising results about human amniotic membrane or its derived cells, in vitro and in vivo, applications in fibrosis, cirrhosis and hepatocellular carcinoma were already published. Since it is an attractive study area, it is becoming a dynamic scientific subject. However, the action mechanisms of human amniotic membrane and its derived cells in hepatic diseases therapy must be precisely known in order that this promising therapy could be clinically used.
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Âmnio/citologia , Âmnio/transplante , Carcinoma Hepatocelular/terapia , Cirrose Hepática/terapia , Neoplasias Hepáticas/terapia , Âmnio/anatomia & histologia , Âmnio/fisiologia , Animais , Carcinoma Hepatocelular/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologiaRESUMO
The present study aims to identify differences between left and right colon adenocarcinoma arising from identical clonal cell and to find out if microenvironment has any influence on matrix metalloproteinase-2 (MMP2), p53 and ß-catenin tumor expressions. MATERIAL AND METHODS. Rats (RNU) were submitted to cecostomy to obtain the orthotopic model of right colon tumor (n = 10), while for the left colon model (n = 10), a colon diversion and distal mucous fistula in the descending colon was used. Cultivated human colon adenocarcinoma cells (WiDr) were inoculated in stomas submucosa. Histopathological analysis, real-time reverse transcription-PCR for ß-catenin, p53 and MMP2, as well as immunohistochemical analysis for p53 and ß-catenin expression were conducted. Central tendency, variance analysis and the Livak delta-delta-CT method were used for statistical analysis, adopting a 5% significance level. RESULTS. All tumors from the left colon exhibited infiltrative ulceration, while in the right colon tumor growth was predominantly exophytic (67%). In the left colon, tumor growth was undifferentiated (100%), while it was moderately differentiated in the right colon (83%). In right colon tumors, MMP2, p53, and ß-catenin gene expressions were higher than compared to left colon (p = 4.59354E-05, p = 0.0035179, p = 0.00093798, respectively, for MMP2, p53 and ß-catenin). ß-catenin and p53 results obtained by real-time polymerase chain reaction were confirmed by immunohistochemistry assay (p = 0.01 and p = 0.001, respectively, for ß-catenin and p53). CONCLUSION. Left and right human colon adenocarcinomas developed in animal models have distinct phenotypes even when they have the same clonal origin. Microenvironment has influenced p53, ß-catenin, and MMP2 expression in animal models of colon cancer.
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Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Microambiente Tumoral , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/genética , Fenótipo , Ratos , Ratos Nus , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/genética , beta Catenina/genéticaRESUMO
Porphyrins are excellent agents for photodynamic treatment of various types of cancer and also good metal chelators that form highly stable metallo-complexes with different radionuclides. Therefore, radiolabelled porphyrins could also be potentially used as tumour imaging agents. In this context, the aim of this work was the radiolabelling of meso-bis[3,4-bis(carboxymethyleneoxy)phenyl]porphyrin, 2CPP, with Technetium-99 m ((99m) Tc) and the evaluation of its radiochemical and biological properties in vitro and in vivo. The labelling procedure was optimized resulting in an efficiency of 92.52 ± 0.48%. The complex (99m) TC-2CPP remained stable for more than 4 h. The biodistribution showed that (99m) Tc-2CPP is eliminated by gastrointestinal and urinary pathways. The tumour/muscle ratio increases over time, being 3.33 ± 1.22 and 3.55 ± 1.29 in WiDr-bearing tumours mice and in H1299-bearing tumours mice, respectively, 6 h post-injection, showing the tumour specificity of the (99m) Tc-2CPP complex. The favourable tumour/muscle ratio of (99m) Tc-2CPP shows that this complex could potentially be used as tumour imaging agent. Moreover, it could be used to follow the progression or regression of tumours before, during and after the radiotherapy, chemotherapy and photodynamic therapy.