Microleakage Evaluation of Temporary Restorations Used in Endodontic Treatment-An Ex Vivo Study.

(1) Background: Coronal microleakage can lead to endodontic treatment failure. This study aimed to compare the sealing ability of different temporary restorative materials used during endodontic treatment. (2) Methods: Eighty sheep incisors were collected, uniformized in length, and access cavities were performed, except for in the negative control group, where the teeth were left intact. The teeth were divided into six different groups. In the positive control group, the access cavity was made and left empty. In the experimental groups, access cavities were restored with three different temporary materials (IRM®, Ketac™ Silver, and Cavit™) and with a definitive restorative material (Filtek Supreme™). The teeth were submitted to thermocycling, and two and four weeks later, they were infiltrated with 99mTcNaO4, and nuclear medicine imaging was performed. (3) Results: Filtek Supreme™ obtained the lowest infiltration values. Regarding the temporary materials, at two weeks, Ketac™ Silver presented the lowest infiltration, followed by IRM®, whereas Cavit™ presented the highest infiltration. At four weeks, Ketac™ Silver remained with the lowest values, whereas Cavit™ decreased the infiltration, comparable to IRM®. (4) Conclusion: Regarding temporary materials, Ketac™ Silver had the lowest infiltration at 2 and 4 weeks, whereas the highest infiltration was found in the Cavit™ group at two weeks and in the IRM® group at 4 weeks.

Application of Perinatal Derivatives on Oncological Preclinical Models: A Review of Animal Studies.

The increasing cancer incidence has certified oncological management as one of the most critical challenges for the coming decades. New anticancer strategies are still needed, despite the significant advances brought to the forefront in the last decades. The most recent, promising therapeutic approaches have benefitted from the application of human perinatal derivatives (PnD), biological mediators with proven benefits in several fields beyond oncology. To elucidate preclinical results and clinic outcomes achieved in the oncological field, we present a narrative review of the studies resorting to animal models to assess specific outcomes of PnD products. Recent preclinical evidence points to promising anticancer effects offered by PnD mediators isolated from the placenta, amniotic membrane, amniotic fluid, and umbilical cord. Described effects include tumorigenesis prevention, uncontrolled growth or regrowth inhibition, tumor homing ability, and adequate cell-based delivery capacity. Furthermore, PnD treatments have been described as supportive of chemotherapy and radiological therapies, particularly when resistance has been reported. However, opposite effects of PnD products have also been observed, offering support and trophic effect to malignant cells. Such paradoxical and dichotomous roles need to be intensively investigated. Current hypotheses identify as explanatory some critical factors, such as the type of the PnD biological products used or the manufacturing procedure to prepare the tissue/cellular treatment, the experimental design (including human-relevant animal models), and intrinsic pathophysiological characteristics. The effective and safe translation of PnD treatments to clinical practice relies on the collaborative efforts of all researchers working with human-relevant oncological preclinical models. However, it requires proper guidelines and consensus compiled by experts and health workers who accurately describe the methodology of tissue collection, PnD isolation, manufacturing, preservation, and delivery to the final user.

Hypoglycaemic and Antioxidant Properties of Acrocomia aculeata (Jacq.) Lodd Ex Mart. Extract Are Associated with Better Vascular Function of Type 2 Diabetic Rats.

Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2). Acrocomia aculeata (Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto-Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg-1 aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H2O2. EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications.

Tumour functional imaging by PET.

Carcinogenesis is a complex multistep process, characterized by changes at different levels, both genetic and epigenetic, which alter cell metabolism. Positron emission tomography (PET) is a very sensitive image modality that allows to evaluate oncometabolism. PET functionalities are immense, since by labelling a molecule that specifically intervenes in a biochemical regulatory pathway of interest with a positron-emitting radionuclide, we can easily image that pathway. Thus, PET makes possible imaging several metabolic processes and assessing risk prediction, screening, diagnosis, response to therapy, metastization and recurrence. In this paper, we provide an overview of different radiopharmaceuticals developed for PET use in oncology, with a focus on brain tumours, breast cancer, hepatocellular carcinoma, neuroendocrine tumours, bladder cancer and prostate cancer because for these cancer types PET has been shown to be valuable. Most of the described tracers are just used in the research environment, with the aim to assess if these tracers could be able to offer an improvement concerning staging/restaging, characterization and stratification of different types of cancer, as well as therapeutic response assessment. In pursuit of personalized therapy, we briefly discuss the more established metabolic tracers and describe recent work on the development of new radiopharmaceuticals, aware that there will continue to exist diagnostic challenges to face modern cancer medicine.

Iodine­131 metabolic radiotherapy leads to cell death and genomic alterations through NIS overexpression on cholangiocarcinoma.

Cholangiocarcinoma (CC) is an aggressive liver tumor with limited therapeutic options. Natrium­iodide symporter (NIS) mediates the uptake of iodine by the thyroid, representing a key component in metabolic radiotherapy using iodine­131 (131I) for the treatment of thyroid cancer. NIS expression is increased in CC, providing the opportunity for a novel therapeutic approach for this type of tumor. Thus, in this study, we aimed to evaluate therapeutic efficacy of 131I in two human CC cell lines. Uptake experiments analyzed the 131I uptake profiles of the tumor cell lines under study. The cells were irradiated with various doses of 131I to evaluate and characterize the effects of metabolic radiotherapy. NIS protein expression was assessed by immunofluorescence methods. Cell survival was evaluated by clonogenic assay and flow cytometry was used to assess cell viability, and the type of death and alterations in the cell cycle. The genomic and epigenetic characterization of both CC cells was performed before and after irradiation. NIS gene expression was evaluated in the CC cells by RT­qPCR. The results revealed that CC cells had a higher expression of NIS. 131I induced a decrease in cell survival in a dose­dependent manner. With the increasing irradiation dose, a decrease in cell viability was observed, with a consequent increase in cell death by initial apoptosis. Karyotype and array comparative genomic hybridization (aCGH) analyses revealed that both CC cell lines were near­triploid with several numerical and structural chromosomal rearrangements. NIS gene expression was increased in the TFK­1 and HuCCT1 cells in a time­dependent manner. On the whole, the findings of this study demonstrate that the presence of NIS in cholangiocarcinoma cell lines is crucial for the decreased cell viability and survival observed following the exposure of cholangiocarcinoma cells to 131I.

Diabetes mellitus and prostate cancer metabolism: Is there a relationship?

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.

Biosimilar medicines - Review.

INTRODUCTION: By definition, biosimilars are similar to a biological reference that has already received marketing authorization for biologic drugs.The purpose of biosimilars is reducing costs, thus increasing access to this treatment, however, the concerns of health professionals and users refer to the fact that to reduce costs will not neglecting the quality, effectiveness and especially security. OBJECTIVE: The aim of this study is then to assess the degree of similarity between the biosimilar and its reference biopharmaceuticals, trying to understand the production process, requirements necessary for approval, and its impact on the quality, safety, efficacy and costs. METHODS: For the systematic review without meta-analysis, we researched articles to the b-on, Pubmed and Medscape to 2005-2014, and selected 23 articles that contributed to the verification of the objectives of this study. RESULTS: Several studies indicate that overall the biosimilar and biological reference showed no significant differences except those inherent to the production process, being the first susceptible to comparability tests demonstrating the similarity in terms of clinical efficacy and safety. CONCLUSION: Biosimilars will be increasingly present in the future as promising therapeutic arsenal and targeted therapy, however, issues related to immunogenicity, interchangeability, automatic substitution and extrapolation of indications should continue to be studied and debated.

The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation.

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.

Effects of X-radiation on lung cancer cells: the interplay between oxidative stress and P53 levels.

Lung cancer (LC) ranks as the most prevalent and deadliest cause of cancer death worldwide. Treatment options include surgery, chemotherapy and/or radiotherapy, depending on LC staging, without specific highlight. The aim was to evaluate the effects of X-radiation in three LC cell lines. H69, A549 and H1299 cell lines were cultured and irradiated with 0.5-60 Gy of X-radiation. Cell survival was evaluated by clonogenic assay. Cell death and the role of reactive oxygen species, mitochondrial membrane potential, BAX, BCL-2 and cell cycle were analyzed by flow cytometry. Total and phosphorylated P53 were assessed by western blotting. Ionizing radiation decreases cell proliferation and viability in a dose-, time- and cell line-dependent manner, inducing cell death preferentially by apoptosis with cell cycle arrest. These results may be related to differences in P53 expression and oxidative stress response. The results obtained indicate that sensibility and/or resistance to radiation may be dependent on molecular LC characteristics which could influence response to radiotherapy and treatment success.

Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine fused chlorins as very active photodynamic agents for melanoma cells.

The development of new stable 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins with high absorption properties at 650 nm, and their impressive photosensitizer ability against melanotic and amelanotic cancer cells is described. Comparison between a diester-substituted chlorin with the corresponding dihydroxymethyl derivative demonstrated that the increased hydrophilicity of the latter is crucial to ensure nanomolar activity against melanoma cells. The new photosensitizer leads to death of human melanoma cells being both apoptosis and necrosis in equal parts involved in the treatment response. The dihydroxymethyl-chlorin was particularly active against human melanocytic melanoma A375 cells, which can be viewed as a solution to overcome the resistance of melanotic melanoma to photodynamic therapy.

The importance of radiotherapy on diffuse large B cell lymphoma treatment: a current review.

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.

Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

Retinoblastoma: might photodynamic therapy be an option?

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.