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Doxorubicin (Dox) is a chemotherapeutic agent widely used in the clinic, whose side effects include cardiotoxicity, associated with decreased antioxidant defenses and increased oxidative stress. The association of Dox with natural antioxidants can extend its use if not interfering with its pharmacological potential. In this study, we aimed to understand the effects and mechanisms of the aqueous extract of Acrocomia aculeata leaves (EA-Aa) in cancer cells and the co-treatment with Dox, in in vitro and in vivo models. It was found that EA-Aa showed a relevant decrease in the viability of cancer cells (K562 and MCF-7) and increased apoptosis and death. The Dox cytotoxic effect in co-treatment with EA-Aa was increased in cancer cells. The therapeutic association also promoted a change in cell death, leading to a higher rate of apoptosis compared to the Dox group, which induced necrosis. In addition, in non-cancer cells, EA-Aa enhanced red blood cell (RBC) redox state with lower hemolysis and malondialdehyde (MDA) content and had no in vitro nor in vivo toxicity. Furthermore, EA-Aa showed antioxidant protection against Dox-induced cytotoxicity in H9c2 cells (cardiomyoblast), partially mediated by the NRF2 pathway. In vivo, EA-Aa treatment showed a relevant decrease in MDA levels in the heart, kidney, and brain, evaluated in C57Bl/6 mice induced to cardiotoxicity by Dox. Together, our results proved the effectiveness of EA-Aa in potentiating Dox anticancer effects, with antioxidant and cardioprotective activity, suggesting EA-Aa as a potential Dox pharmacological adjuvant.

Background: Microorganisms and their by-products are responsible for establishing pulpal and periapical diseases. Healing is compromised in patients under bisphosphonate therapy, and the presence of periapical infections can potentially lead to the development of medication-related osteonecrosis of the jaw (MRONJ). This work aimed to evaluate if bisphosphonate therapy is a risk factor for MRONJ development in the presence of periapical lesions. Methods: Two groups of 10 female Wistar rats were used. The experimental group received zoledronate (0.1 mg/kg) intraperitoneally, and the control received a saline solution, three times a week for three weeks. One week after the last injection, apical periodontitis was induced through pulpal exposure in the mandibular first molars. Twenty-one days later, the animals were intravenously injected with 99mTc-HMDP, and the radioactivity uptake by mandibular specimens was counted. In addition, sample radiographs and a histological examination were performed. Results: The bone loss was higher in the control group when compared to the experimental group (p = 0.027). 99mTc-HMDP uptake in the control was reduced compared with the experimental group, although without statistical significance. Conclusions: In the presence of zoledronate therapy, apical periodontitis does not increase the risk of MRONJ development, and periapical lesions have lower bone resorption when compared to the control group.

(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.

Abstract Colorectal cancer is a worldwide health burden, with high incidence and mortality, especially in the advanced stages of the disease. Preclinical models are very important and valuable to discover and validate early and specific biomarkers as well as new therapeutic targets. In order to accomplish that, the animal models must replicate the clinical evolution of the disease in all of its phases. In this article, we review the existent mouse models, with their strengths and weaknesses in the replication of human cancer disease progression, with major focus on orthotopic models.

Hybrid bioactive composite resins combine the benefits of glass ionomer cements with composite resins. Its self-adhesiveness is achieved through functional polyacrylic acids and carboxylic groups, hybridizing the smear layer and establishing ionic interactions between calcium and dentin. These materials are defined as having good aesthetics, moisture tolerance, durability, simplicity in technique and handling and are able to maintain a low microfiltration rate while releasing calcium, phosphate and fluorine. The aim of the present study was to evaluate microleakage in restorations using Surefill One™ bioactive resin. The null hypothesis is that this type of resin does not obtain a lower microleakage rate when compared to other materials. An in vitro study was carried out using thirty-six premolars and molars extracted for orthodontic reasons. Identical preparations were thus performed in all of them (Class V with 4 mm mesio-distal, 3 mm occluso-gingival and 3 mm in depth) and divided into different experimental groups: one positive control, one negative control and two tests with bioactive composite resin and conventional composite resin (Surefill One™ and Spectra™ ST HV, respectively). Through quantitative techniques using nuclear medicine, it was possible to evaluate microleakage through the use of a radioactive isotope, technetium. Radioactivity emitted by the specimens was detected by a gamma camera. The different groups were compared using the Kruskal–Wallis test and the Games–Howell test for multiple comparisons. The results of the experimental study point to statistically significant differences between the test groups (p = 0.002) with increased microleakage in the bioactive composite resin group. Based on the present microleakage study, it was possible to conclude that the bioactive composite resin (Surefill One™) does not reduce the microleakage rate when compared to a conventional nanohybrid composite resin (Spectra™ ST HV). However, Surefill One™ can be used in temporary restorations, primary teeth and in cases of tissue remineralization, thus avoiding more invasive procedures.

Background: Obturation represents a critical step in endodontic treatment, which relies on a core material and a sealer. This study aims to evaluate the sealing ability and bond strength to the root canal walls of an epoxy resin-based sealer (AH-Plus®, Dentsply Sirona, Johnson City, TN, USA) and a bioceramic sealer (GuttaFlow Bioseal®, Coltène/Whaledent, GmbH + Co. KG, Langenau, Germany). Methods: Thirty-eight maxillary anterior teeth with single roots and identical round sections were separated into two experimental groups according to the root canal sealers used, namely, G1 = AH-Plus® and G2 = GuttaFlow Bioseal®, and two control groups, specifically, G3 = the negative control and G4 = the positive control. The sealing capacity was measured by the penetration of the radioactive isotope 99mTc. For the push-out test, the compressive force test was performed in a universal machine and the force was applied by exerting pressure on the surface of the material to be tested in the apical to the coronal direction and using three test points with different diameters. Results: GuttaFlow Bioseal® exhibited superior sealing ability compared to AH-Plus® (p = 0.003). Regarding the bond strength, AH-Plus® provided higher adhesion values than GuttaFlow Bioseal® in the three sections of the tooth root (p = 0.001). Conclusions: GuttaFlow Bioseal® had significantly better sealing ability than AH-Plus® but lower adhesion values in the three zones of the root canal, with statistically significant differences between the groups. However, it is important to note that for the action of endodontic sealers to be maximized, the root-filling technique must be most appropriate.

Colorectal cancer (CRC) is a major health burden and may arise as a complication of solid organ transplantation. Our study aimed to assess the incidence of the CRC in kidney and liver transplanted patients at a tertiary and reference center and to describe their clinical and pathological features.Twelve patients, 10 men and two women, with a mean age of 60 years, composed our cohort, ten of them submitted to CRC resection. Transplanted organ was liver in five patients and kidney in seven. Regarding overall survival, patients submitted to renal transplantation were all deceased 5 years after CRC diagnosis, while those subjected to hepatic transplantation had a survival of 60% at the fifth year.Pathology examination showed seven patients with advanced disease (stage III/IV) and high amount of necrosis. Tumor microenvironment was disturbed, with low inflammatory infiltrate, absence of natural killer cells and no PD-L1 expression. CRC exhibited microsatellite instability in 40%, with expression of cancer stem cell markers (CD133, CD44 and ALDH1), as well as P53 (50%) and KRAS mutations (41.7%).CRC cancer after kidney and hepatic transplantation is a rare, but aggressive and deadly event. Regular follow-up should be instituted in these patients.

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.

Abstract Purpose: To investigate the inflammatory and redox responses to teduglutide on an animal model of laparotomy and intestinal anastomosis. Methods: Wistar rats (n=62) were allocated into four groups: “Ileal Resection and Anastomosis” vs. “Laparotomy”, each one split into “Postoperative Teduglutide Administration” vs. “No Treatment”; and euthanized at the third or the seventh day. Ileal and blood samples were recovered at the baseline and at the euthanasia. Flow cytometry was used to study the inflammatory response (IL-1α, MCP-1, TNF-α, IFN-γ and IL-4 levels), oxidative stress (cytosolic peroxides, mitochondrial reactive species, intracellular glutathione and mitochondrial membrane potential) and cellular viability and death (annexin V/propidium iodide double staining). Results: Postoperative teduglutide treatment was associated with higher cellular viability index and lower early apoptosis ratio at the seventh day; higher cytosolic peroxides level at the third day and mitochondrial overgeneration of reactive species at the seventh day; higher tissue concentration of IL-4 and lower local pro-to-anti-inflammatory cytokines ratio at the seventh day. Conclusion: Those findings suggest an intestinal pro-oxidative and anti-inflammatory influence of teduglutide on the peri-operative context with a potential interference in the intestinal anastomotic healing.

Introduction: Excessive portal venous pressure in the liver remnant is an independent factor in the occurrence of posthepatectomy liver failure and small-for-size syndrome. The baseline portal pressure prior to hepatectomy was not considered previously. The aim of this study is to assess the impact of portal pressure change during hepatectomy on the patient outcome. Material and Methods: Prospective observational study including 30 patients subjected to intraoperative measurement of portal pressure before and after hepatectomy. This variation was related to the patient outcome. Control group evaluation was assessed. Patient, disease and procedure features were considered. The optimal cut-off of portal pressure variation was determined. Linear regression or logistic regression was applied to identify predictors of the outcome. Results: The univariate analysis showed that portal pressure increase after hepatectomy was associated with coagulation impairment in the first 30 postoperative days (p < 0.05), and with the occurrence of major complications (p = 0.01), namely hepatic failure (p = 0.041). The multivariate analysis showed that portal venous pressure increase ≥ 2 mmHg is an independent factor for worse outcomes. Discussion: As in previous studies, this study concludes that, after hepatectomy, in addition to the functional liver remnant, other factors are responsible for deterioration of liver function and patient outcome, such as the portal pressure increase and the exposure to chemotherapy prior to hepatectomy. This work may influence the definition of future indications for portal influx modulation. Conclusion: Patient outcomes are influenced by the portal venous pressure increase: an increment ≥ 2 mmHg after hepatectomy seems to increase the risk of major complications.

Acute pancreatitis (AP) is an inflammatory process of the pancreas with variable involvement of the pancreatic and peripancreatic tissues and remote organ systems. The main goal of this study was to evaluate the inflammatory biomarkers, oxidative stress (OS), and plasma metabolome of patients with different degrees of biliary AP severity to improve its prognosis. Twenty-nine patients with biliary AP and 11 healthy controls were enrolled in this study. We analyzed several inflammatory biomarkers, multifactorial scores, reactive oxygen species (ROS), antioxidants defenses, and the plasma metabolome of biliary AP and healthy controls. Hepcidin (1.00), CRP (0.94), and SIRI (0.87) were the most accurate serological biomarkers of AP severity. OS played a pivotal role in the initial phase of AP, with significant changes in ROS and antioxidant defenses relating to AP severity. Phenylalanine (p < 0.05), threonine (p < 0.05), and lipids (p < 0.01) showed significant changes in AP severity. The role of hepcidin and SIRI were confirmed as new prognostic biomarkers of biliary AP. OS appears to have a role in the onset and progression of the AP process. Overall, this study identified several metabolites that may predict the onset and progression of biliary AP severity, constituting the first metabonomic study in the field of biliary AP.

The need for effective and safe therapies for cancer is growing as aging is modifying its epidemiology. Cold atmospheric plasma (CAP) has gained attention as a potential anti-tumor therapy. CAP is a gas with enough energy to ionize a significant fraction of its constituent particles, forming equal numbers of positive ions and electrons. Timely-resolved output voltage measurement, emission spectroscopy, and quantification of reactive species (RS) in plasma-activated media (PAM) were performed to characterize the physical and chemical properties of plasma. To assess the cytotoxicity of cold atmospheric plasma in human tumors, different cell lines were cultured, plated, and exposed to CAP, followed by MTT and SRB colorimetric assays 24 h later. Human fibroblasts, phenotypically normal cells, were processed similarly. Plasma cytotoxicity was higher in cells of breast cancer, urinary bladder cancer, osteosarcoma, lung cancer, melanoma, and endometrial cancer. Cytotoxicity was time-dependent and possibly related to the increased production of hydrogen peroxide in the exposed medium. Sixty seconds of CAP exposure renders selective effects, preserving the viability of fibroblast cells. These results point to the importance of conducting further studies of the therapy with plasma.

PURPOSE: To investigate the impact of selective hepatic artery clamping (SHAC) in hepatocellular function. METHODS: Three groups of Wistar male rats were subjected to SHAC ischemia period of 60min: Group A continuous SHAC were subjected to SHAC ischemia period of 60min, Group B intermittent SHAC of 30min with 5min of reperfusion and Group C intermittent SHAC of 15min with 5min of reperfusion. Animals without SHAC were included-Group D. To evaluate hepatocellular function blood markers and hepatic extraction function (HEF) using 99mTc-mebrofenin were performed before and after surgery. Flow cytometry was used to analyze oxidative stress and cell viability. RESULTS: A mortality rate of 7.6% in Group A was observed. HEF maintained normal values between the groups. Flow cytometry demonstrated no significant differences between the groups in viability, type of cell death as well as in the production of reactive oxygen species. CONCLUSIONS: The selective hepatic artery clamping compared to other clamping techniques results on increased cell viability and decreased hepatocyte death. The SHAC is a potential alternative to decrease per-operative bleeding while maintaining hepatocellular function.

Hepatocellular carcinoma (HCC) is increasingly considered an issue of global importance. Its rates of incidence and mortality have been markedly increasing over the last decades. Among risk factors, some should be highlighted, namely the infections by hepatitis B and C virus, as well as clinical cases of cirrhosis. HCC is characterized as asymptomatic disease in the initial stages which most often leads to a late diagnosis. At molecular and genetic level HCC represents a highly complex tumor entity, including a wide variety of mutations, thus accounting for different mechanisms of resistance towards therapeutic approaches. In particular, mutations of the TP53 gene, as well as a deregulation between the expression of pro- and anti-apoptotic proteins of the BCL-2 family are observed. Regarding treatment modalities, surgical procedures offer the best chance of cure, however, due to a late diagnosis, most of concerned patients cannot be subjected to them. Chemotherapy and radiotherapy are also ineffective, and currently, the treatment with sorafenib is the most commonly used systemic therapy although it can only increase the patient survival for some months. In this sense, a quick and accurate investigation is of utmost importance in order to develop ways of early diagnosis as well as new therapies for HCC.

PURPOSE: The present a novel adenocarcinoma model in athymic mice. METHODS: Seven athymic mice were used. Colon diversion and distal fistula were made. Adenocarcinoma cells were inoculated in the submucosa of fistula. Tumor growth was monitored daily. Scintigraphy with 99mTc-MIBI was performed to identify the tumor. RESULTS: The model of distal colon cancer is feasible. Tumor detection was possible by both, macroscopically and molecular imaging. All resections demonstrated poorly differentiated tumors. Colon obstruction occurred in one case, similarly to evolution in human tumors of distal colon. CONCLUSION: The proposed model of distal colon cancer is feasible, allows for easy monitoring of tumoral growth by both, macroscopically and molecular imaging, and is suitable for studying the evolution of tumor with implementation of cytotoxic therapy in vivo.OBJETIVO: Apresentar novo modelo de adenocarcinoma distal em camundongos atímicos. MÉTODOS: Foram utilizados sete camundongos atímicos. Desvio do cólon distal e fístula foram feitas. Células de adenocarcinoma foram inoculadas na submucosa da fístula. O crescimento do tumor foi monitorado diariamente. Cintilografia com 99mTc-MIBI foi realizada para identificar o tumor. RESULTADOS: O modelo de câncer de cólon distal é viável. Detecção do tumor foi possível macroscopicamente e por imagem molecular. Todas as ressecções demonstraram tumores pouco diferenciados. Obstrução do cólon ocorreu em um caso, de forma semelhante à evolução em tumores humanos do cólon distal. CONCLUSÃO: O modelo de câncer do cólon distal proposto é viável, permite a monitorização fácil do crescimento tumoral macroscopicamente e por imagem molecular, sendo adequado para o estudo da evolução de tumor com aplicação de terapia citotóxica in vivo.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe complication that has recently emerged in patients treated with intravenous bisphosphonates for malignant diseases. This complication usually presents after a minor local trauma during a dental treatment. Several etiopathogenic mechanisms of this pathological condition have been proposed, but no model can explain all morphological changes observed at the macroscopic and microscopic level. BRONJ is likely to be related to direct toxicity in the bone and soft tissue cells, due to nitrogen-containing bisphosphonates. This review elucidates the clinical indications and mechanism of action of bisphosphonates, reports some clinical diagnostic criteria for BRONJ, describe the histopathological criteria for BRONJ diagnosis, the potential triggering pathways and the available treatment strategies.

Magnetic resonance spectroscopy (MRS) is one of the most powerful analytical techniques, being frequently used to derive physical, chemical, electronic, and structural information about molecules. Considering its potentialities and its evolution as cell/tissue response predictor, it can be used to detect changes in the tumor pathophysiology before, during, and after treatment. Of particular relevance to this analysis, due to its higher sensitivity, is proton magnetic resonance spectroscopy (1H-MRS) either applied directly in vivo or by using tumor biopsies and high-rotation magic angle spinning (HRMAS). Several metabolites have been quantified in several tumors, including creatine and phosphocreatine, choline, lactate and myoinositol, and used for distinguishing different cancer types. Several advantages characterize this technique including swiftness and ability to support the characterization of tumoral lesions on the basis of their biochemical composition, which may provide additional diagnostic and prognostic information as an adjunct to routine histological assessment. Many tumors have already been studied by 1H-MRS, and there is growing interest in studying others in order to establish extended metabolite databases which could help in their identification and characterization.

Tumoral hypoxia is related to severe structural abnormalities of tumor microvessels, leading to deteriorated O2 diffusion. This decreased O2 concentration in cancer cells compromises cellular functions, besides being responsible for resistance to radiation therapy. Consequently, it is very important to know the hypoxic status of a tumor. In this review, the different methodologies available for evaluating cellular hypoxia in vivo are discussed, particularly those in which the hypoxia information is obtained through imaging. Among these the nuclear medicine approach uses ligands to complex with radionuclides. The resulting radioactive complexes which may be single photon or positron emitters, are very useful as imaging probes. The nature of ligands and their corresponding complexes, with application or potential application as hypoxia detectors, will be described. A summary of the most significant results so far obtained in clinical or preclinical applications will also be discussed.

Polysemy is the phenomenon of co-existence of multiple senses within one single linguistic expression. It is also the core issue of Augusto Soares da Silva’s anthology of essays on “the world of meanings in Portuguese”, which sums up more than 15 years of research on polysemy, semantics and cognition. As the subtitle suggests, the author’s approach to the phenomenon of related meanings is a cognitive one. This means that beyond the description of linguistic meanings and the way they are inventoried in single linguistic expressions, the author is concerned with the underlying cognitive operations that establish and stabilize the relations between meanings and that allow for these different meanings to be expressed by the same linguistic form. In other words, the fact that different meanings are conveyed by one single expression reveals an underlying schematic relatedness which sustains the often apparent arbitrariness in the linguistic reference.