Publications by authors named "Hugo Duarte"

21 Publications

  • Page 1 of 1

Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 12 15;22(12):1752-1763. Epub 2021 Nov 15.

Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, Netherlands.

Background: The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results.

Methods: This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239.

Findings: From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up.

Interpretation: Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up.

Funding: Advanced Accelerator Applications, a Novartis company.
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http://dx.doi.org/10.1016/S1470-2045(21)00572-6DOI Listing
December 2021

Clinical Decision-Making in Nursing Scale (CDMNS-PT©) in nursing students: translation and validation.

Rev Bras Enferm 2021 1;74(suppl 6):e20210032. Epub 2021 Sep 1.

Escola Superior de Saúde, Instituto Politécnico de Leiria. Leiria, Portugal.

Objectives: to validate, for the Portuguese population, the Clinical Decision-Making Nursing Scale© (CDMNS©).

Methods: this methodological study involved 496 nursing students who filled in a questionnaire created using sociodemographic and academic data, and the scale to evaluate the making of decisions in nursing.

Results: the confirmatory factorial analysis showed that the adjustment of the factorial structure has good quality, being made up by three factors (X2/gl = 2.056; GFI = 0.927; CFI = 0.917; RMSEA = 0.046; RMR = 0.039; SRMR = 0.050). For the scale to be reliable, it had to include only the reliability of the scale required it to be constituted by 23 items, with correlation values that varied from 0.184 and 0.610, and a global Cronbach's Alpha of 0.851, which showed its good reliability.

Conclusions: the CDMNS-PT© is valid and reliable, showing a high potential to be used in clinical practice and investigation.
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http://dx.doi.org/10.1590/0034-7167-2021-0032DOI Listing
September 2021

Improved survival in patients with thyroid function test abnormalities secondary to immune-checkpoint inhibitors.

Cancer Immunol Immunother 2021 Feb 25;70(2):299-309. Epub 2020 Jul 25.

Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.

Immune-checkpoint inhibitors (ICI) are monoclonal antibodies which target molecules to enhance antitumor response. Several adverse events have been described and the major ICI-related endocrinopathies are thyroid dysfunction and hypophysitis. Its occurrence has been associated with improved outcomes, but it is still to be proven. We performed a retrospective study of patients treated with ICI between 2014 and 2019 at an oncologic center to characterize thyroid function test abnormalities (TFTA) and to evaluate clinical outcomes. We excluded patients without regular monitoring of thyroid function, with previous thyroid or pituitary disease, previous head/neck radiotherapy and who performed only one ICI cycle. We included 161 of 205 patients treated with pembrolizumab, nivolumab or ipilimumab for several neoplasms, with a median duration of 18.9 weeks (9.1-42.6) of ICI treatment and 49.4 weeks (26.5-75.8) of follow-up. New-onset TFTA was diagnosed in 18% of patients (n = 29), in median at 10.6 weeks (6.1-31.1) of ICI therapy. On the whole, 8.7% had primary hypothyroidism, 4.3% central hypothyroidism, 2.5% biphasic thyroiditis and 2.5% thyrotoxicosis. Patients who experienced primary or central thyroid dysfunction had a significantly improved overall response rate (58.6% vs 34.2%, p = 0.015) and overall survival (3.27 vs 1.76 years, p = 0.030), compared to the control group. The risk of mortality was two times higher for control group (adjusted HR = 2.43, 95% CI 1.13-5.23, p = 0.023). This study recognizes that primary and central thyroid dysfunction can be a predictive clinical biomarker of a better response to ICI across several neoplasms.
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http://dx.doi.org/10.1007/s00262-020-02664-yDOI Listing
February 2021

Ga-DOTANOC and F-FDG PET/CT in metastatic medullary thyroid carcinoma: novel correlations with tumoral biomarkers.

Endocrine 2019 05 25;64(2):322-329. Epub 2019 Jan 25.

Nuclear Medicine Department, Instituto Português de Oncologia do Porto, Porto, Portugal.

Objective: Metastatic disease is common in medullary thyroid carcinoma (MTC) and it is usually detected by raising calcitonin and carcinoembryonic antigen (CEA) levels. Nuclear medicine imaging has an important role in lesion identification/characterisation. We aim to compare Ga-DOTANOC PET/CT and F-FDG PET/CT performance and to explore the correlations between tumoral markers and functional imaging.

Methods: This a retrospective cross-sectional study including 13 patients with MTC and high calcitonin/CEA levels that underwent both Ga-DOTANOC PET/CT and F-FDG PET/CT.

Results: Ga-DOTANOC PET/CT identified MTC metastases in 2twopatients that were F-FDG-negative (sensitivity of 69.2% vs. 53.9%, respectively). Ga-DOTANOC PET/CT also detected a higher number of lesions than F-FDG PET/CT in seven patients, with only one patient showing the opposite pattern. Both differences lacked statistical significance (p = 0.50 and p = 0.86, respectively) but Ga-DOTANOC PET/CT better performance allowed changes in patients' management. Ga-positive/F-FDG-negative patients were the ones with the lowest calcitonin doubling time and presented a CEA doubling time >24 months, while the patient with more F-FDG-positive lesions was the one with the highest CEA/calcitonin ratio. The number of lesions found in Ga-DOTANOC PET/CT were correlated with calcitonin levels (r = 0.73; p < 0.01) but not with CEA ones (r = 0.42; p = 0.15). The number of F-FDG hypermetabolic focus were correlated with CEA levels (r = 0.60; p < 0.05) but not with calcitonin (r = 0.48; p = 0.09).

Conclusions: This is the first study to describe a positive correlation between Ga-positive lesions and calcitonin levels and between F-FDG-positivity and CEA levels. Tumoral markers pattern in metastatic MTC could help clinicians to decide which exam to perform first.
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http://dx.doi.org/10.1007/s12020-019-01846-8DOI Listing
May 2019

Metabolic Activity in the Visceral and Subcutaneous Adipose Tissues by FDG-PET/CT in Obese Patients.

Acta Med Port 2017 Nov 29;30(11):813-817. Epub 2017 Nov 29.

Serviço de Medicina Nuclear. Instituto Português de Oncologia do Porto. Porto. Portugal.

Introduction: The emerging role of the 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in the study of the metabolic activity and inflammation in adipose tissue indicates that it might be a reliable tool to complement the risk stratification in obesity. The aims of this study were the evaluation of 18F-fluorodeoxyglucose uptake by visceral adipose tissues and subcutaneous adipose tissues and to determine eventual differences in patients with and without obesity.

Material And Methods: Retrospective study of adult patients who underwent whole body 18F-fluorodeoxyglucose-positron emission tomography/ computed tomography scanning between July and August of 2016.

Statistical Analysis: SPSS™ software v.20. Statisticalsignificance: p < 0.05.

Results: We assessed fluorodeoxyglucose-positron emission tomography/computed tomography scans from 156 patients (58.3% of males) with a mean age of 61.0 ± 14.1 years. Half of the patients had a body mass index ≥ 25.0 kg/m2 and 15.4% (n = 24) were obese. In both groups, the mean 18F-fluorodeoxyglucose uptake was higher in visceral adipose tissues. There were no differences in 18F-fluorodeoxyglucose uptake in visceral adipose tissues between the groups. Obese patients had lower density of adipose tissue,both in subcutaneous adipose tissues and in visceral adipose tissues. Abdominal circumference and density of visceral adipose tissueshad a positive predictive value in the mean 18F-fluorodeoxyglucose uptake in visceral adipose tissues. Discussion: Through a non-invasive test, this study demonstrated a significant higher metabolic activity in visceral adipose tissues in both obese and non-obese patients. According to our results, abdominal circumference was an important determinant in 18F-fluorodeoxyglucose uptake in visceral adipose tissues. We also demonstrated that obese patients had differences in adipose tissue quality.

Conclusion: Our findings reinforce the importance of the adipose tissue quality and distribution for metabolic risk stratification.
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http://dx.doi.org/10.20344/amp.8712DOI Listing
November 2017

[Treatment of Gastroenteropancreatic Neuroendocrine Tumors with 177Lu-DOTA-TATE: Experience of the Portuguese Institute of Oncology in Porto].

Acta Med Port 2016 Nov 30;29(11):726-733. Epub 2016 Nov 30.

Serviço de Medicina Nuclear. Instituto Português de Oncologia. Porto. Portugal.

Introduction: The purpose of this article is to report the experience of the Portuguese Institute of Oncology - Porto in the treatment of gastroenteropancreatic neuroendocrine tumors with 177Lu-DOTA-TATE, regarding the safety and efficacy of this treatment modality.

Material And Methods: A retrospective analysis of clinical reports of patients with gastroenteropancreatic neuroendocrine tumors undergoing treatment with 177Lu-DOTA-TATE between April 2011 and November 2013 was performed.

Results: Thirty six cases were reviewed and 30 completed all 3 cycles of 177Lu-DOTA-TATE (83.3%). In these patients it was registered: acute side effects in 8.9% of cycles; grade 3 CTCAE liver toxicity in 13.3% of patients (all with previous abnormal liver function); absence of significant renal or hematologic toxicity; symptomatic improvement in 71.4% of patients; median overall time to progression of 25.6 months; median overall survival from diagnosis of 121.7 months. Patients with higher expression of somatostatin receptors had longer progression-free survival and overall survival times (p < 0.05).

Discussion: Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE is an effective, safe and well-tolerated treatment, as evidenced in our study by the following findings: symptomatic improvement in most patients and increased time to disease progression and survival (especially in those with higher sstr expression), with acute and significant subacute/chronic side effects reported only in a minority of cases.

Conclusion: Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE is a promising treatment for patients with gastroenteropancreatic neuroendocrine tumors, with demonstrated benefits in terms of safety and efficacy.
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http://dx.doi.org/10.20344/amp.7306DOI Listing
November 2016

An artificial neural networks approach for assessment treatment response in oncological patients using PET/CT images.

BMC Med Imaging 2017 02 13;17(1):13. Epub 2017 Feb 13.

IPO-Porto Research Centre (CI-IPOP), Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal.

Background: Positron Emission Tomography - Computed Tomography (PET/CT) imaging is the basis for the evaluation of response-to-treatment of several oncological diseases. In practice, such evaluation is manually performed by specialists, which is rather complex and time-consuming. Evaluation measures have been proposed, but with questionable reliability. The usage of before and after-treatment image descriptors of the lesions for treatment response evaluation is still a territory to be explored.

Methods: In this project, Artificial Neural Network approaches were implemented to automatically assess treatment response of patients suffering from neuroendocrine tumors and Hodgkyn lymphoma, based on image features extracted from PET/CT.

Results: The results show that the considered set of features allows for the achievement of very high classification performances, especially when data is properly balanced.

Conclusions: After synthetic data generation and PCA-based dimensionality reduction to only two components, LVQNN assured classification accuracies of 100%, 100%, 96.3% and 100% regarding the 4 response-to-treatment classes.
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http://dx.doi.org/10.1186/s12880-017-0181-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307785PMC
February 2017

Pulsed electromagnetic field therapy effectiveness in low back pain: A systematic review of randomized controlled trials.

Porto Biomed J 2016 Nov-Dec;1(5):156-163. Epub 2016 Nov 1.

Clínica do Dragão, Espregueira-Mendes Sports Centre - FIFA Medical Centre of Excellence, Porto, Portugal.

Background: Low back pain is a worldwide prevalent musculoskeletal condition in the general population. In this sense, the pulsed electromagnetic fields (PEMF) therapy has shown significant clinical benefits in several musculoskeletal conditions.

Objective: To assess the effectiveness of the PEMF therapy in reducing pain and clinical symptomatology in patients with low back pathological conditions.

Methods: It was performed a comprehensive database search using Pubmed, Scopus, Cochrane Library and PEDro databases to assess the effectiveness of the PEMF therapy in reducing pain and clinical symptomatology in patients with low back pathological conditions. The search was performed from January 2005 to August 2015 and conducted by two independent investigators, which scrutinize the reference list of most relevant studies. The methodological quality was assessed by the PEDro scale and the level of evidence was set according Oxford Center for Evidence-Based Medicine scale.

Results: Six studies were eligible inclusion on the qualitative analysis and five into the quantitative analysis, scoring an overall 6.8 points according the PEDro scale. The studies showed heterogeneity concerning the intervention protocols. Nevertheless, the effect sizes' indicated a clear tendency to reduction of the pain intensity favoring the PEMF groups, reaching a minimal clinically important difference.

Conclusion: PEMF therapy seems to be able to relieve the pain intensity and improve functionality in individuals with low back pain conditions. Further research is needed regarding PEMF effects on the different conditions of low back pain, with standardized protocols, larger samples and adjustment for low back pain confounders in order to achieve stronger conclusions.
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http://dx.doi.org/10.1016/j.pbj.2016.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806956PMC
November 2016

On cellulose dissolution and aggregation in aqueous tetrabutylammonium hydroxide.

Biomacromolecules 2016 09 12;17(9):2873-81. Epub 2016 Aug 12.

Faculty of Sciences and Technology (MeditBio), University of Algarve , Campus de Gambelas, Ed. 8, 8005-139 Faro, Portugal.

Aqueous tetrabutylammonium hydroxide, TBAH(aq), has been found to dissolve cellulose and to be a potential solvent for chemical processing or fiber spinning. In this paper, we have investigated the dissolution state of cellulose in 40 wt % TBAH(aq) solvent, and present an extensive study of rheology, combined with static light and small-angle X-ray scattering, to correlate cellulose aggregation with changes in the rheological parameters. Two cellulose molecular weights are compared. Microcrystalline cellulose (MCC), with a degree of polymerization of ca. 260, and a dissolving pulp with an approximately ten times higher molecular weight. Scattering data demonstrate that cellulose is molecularly dissolved at lower cellulose concentrations, while aggregates are present when the concentration exceeds a certain value. The onset of the aggregate formation is marked by a pronounced increase in the scattering intensity at low q, shear thinning behavior and violation of the empirical Cox-Merz rule. Additionally, the SAXS data suggest the presence of a solvation shell enriched in TBA(+) ions, compared to the bulk solvent. The results are consistent with the recent suggestion that while native cellulose I may still dissolve, solutions are, above a particular concentration, becoming supersaturated with respect to the more stable crystal form cellulose II.
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http://dx.doi.org/10.1021/acs.biomac.6b00696DOI Listing
September 2016

The role of cyclodextrin-tetrabutylammonium complexation on the cellulose dissolution.

Carbohydr Polym 2016 Apr 24;140:136-43. Epub 2015 Dec 24.

CQC, University of Coimbra, Department of Chemistry, 3004-535 Coimbra, Portugal.

Cellulose dissolution is a challenging process which is typically very sensitive to the solvent characteristics such as pH, temperature or presence of additives. Regarding the later aspect, it is here reported the interaction between α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD) with the tetrabutylammonium cation (TBA(+)) by (1)H NMR titration experiments. The analysis by the continuous variation method suggests the formation of 1:1 CD:TBA(+) complexes. However, the computed apparent association constants reveal that the interaction of TBA(+) with the β-CD (K=1580M(-1)) is unexpectedly stronger than with α-CD (K=106M(-1)). In both CD cases, the formation of CD:TBA(+) complexes decrease the dissolution efficiency of the solvent and this has been rationalized as an effective decrease in the concentration of the amphiphilic cation and concomitant weakening of the hydrophobic interactions in solution influencing the overall performance of the solvent. Additionally, the data also supports the fact that amphiphilic species in solution are beneficial for the enhancement of cellulose solubility.
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http://dx.doi.org/10.1016/j.carbpol.2015.12.026DOI Listing
April 2016

Cardiomyocyte dysfunction during the chronic phase of Chagas disease.

Mem Inst Oswaldo Cruz 2013 Apr;108(2):243-5

Laboratório de Membranas Excitáveis e Biologia Cardiovascular, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of heart failure. We investigated modifications in the cellular electrophysiological and calcium-handling characteristics of an infected mouse heart during the chronic phase of the disease. The patch-clamp technique was used to record action potentials (APs) and L-type Ca2+ and transient outward K+ currents. [Ca2+]i changes were determined using confocal microscopy. Infected ventricular cells showed prolonged APs, reduced transient outward K+ and L-type Ca2+ currents and reduced Ca2+ release from the sarcoplasmic reticulum. Thus, the chronic phase of Chagas disease is characterised by cardiomyocyte dysfunction, which could lead to heart failure.
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http://dx.doi.org/10.1590/0074-0276108022013019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970661PMC
April 2013

Novel insights into the development of chagasic cardiomyopathy: role of PI3Kinase/NO axis.

Int J Cardiol 2013 Sep 29;167(6):3011-20. Epub 2012 Sep 29.

Laboratórios de Membranas Excitáveis e de Biologia Cardiovascular, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Background: Chagas' disease is one of the leading causes of heart failure in Latin American countries. Despite its great social impact, there is no direct evidence in the literature explaining the development of heart failure in Chagas' disease. Therefore, the main objective of the study was to investigate the development of the Chagas' disease towards its chronic phase and correlate with modifications in the cellular electrophysiological characteristics of the infected heart.

Methods And Results: Using a murine model of Chagas' disease, we confirmed and extended previous findings of altered electrocardiogram and echocardiogram in this cardiomyopathy. The observed changes in the electrocardiogram were correlated with the prolonged action potential and reduced transient outward potassium current density. Reduced heart function was associated with remodeling of intracellular calcium handling, altered extracellular matrix content, and to a set of proteins involved in the control of cellular contractility in ventricular myocytes. Furthermore, disruption of calcium homeostasis was partially due to activation of the PI3Kinase/nitric oxide signaling pathway. Finally, we propose a causal link between the inflammatory mediators and heart remodeling during chagasic cardiomyopathy.

Conclusion: Altogether our results demonstrate that heart failure in Chagas' disease may occur due to electrical and mechanical remodeling of cardiac myocytes, and suggest that AKT/PI3K/NO axis could be an important pharmacological target to improve the disease outcome.
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http://dx.doi.org/10.1016/j.ijcard.2012.09.020DOI Listing
September 2013

Chronic exercise partially restores the transmural heterogeneity of action potential duration in left ventricular myocytes of spontaneous hypertensive rats.

Clin Exp Pharmacol Physiol 2012 Feb;39(2):155-7

Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

Hypertension leads to electrophysiological changes in the heart. Chronic exercise induced by a treadmill-running programme (TRP) is considered a potential non-pharmacological treatment for hypertension and may have implications in heart remodelling. However, it is not known whether the TRP is able to improve the electrophysiological properties of the heart in spontaneously hypertensive rats (SHR). In the present study, we investigated whether TRP affects the electrical properties of left ventricular (LV) myocytes isolated from different layers of the LV wall of SHR. Male SHR were divided into exercised (chronic treadmill running for 8 weeks; CEX-SHR) and sedentary (SED-SHR) groups. Age-matched normotensive Wistar male rats served as controls. Action potentials (AP) and transient outward potassium current (I(to) ) were recorded in subepicardial (EPI) and subendocardial (ENDO) LV myocytes. In normotensive controls, AP duration (APD) was longer in ENDO cells than in EPI cells. This sort of transmural heterogeneity in the LV was not observed in sedentary SHR and was partially restored in SHR subject to chronic exercise. This partial recovery was associated with an increase in I(to) density in EPI cells but not in ENDO cells. The electrophysiological changes observed in the CEX-SHR group were not accompanied by either amelioration of systolic blood pressure or a reduction in heart hypertrophy. These findings imply that a TRP is able to improve the electrophysiological parameters of isolated cardiac myocytes in SHR. This sort of adaptation contributes to the overall improvement of heart physiology in this model.
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http://dx.doi.org/10.1111/j.1440-1681.2011.05669.xDOI Listing
February 2012

Investigation of the cardiomyocyte dysfunction in bradykinin type 2 receptor knockout mice.

Life Sci 2010 Dec 21;87(23-26):715-23. Epub 2010 Oct 21.

Laboratório de Membranas Excitáveis e Biologia Cardiovascular, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Aims: Bradykinin type 2 receptor (B(2)R) is the key component to trigger the intracellular signaling pathway in response to bradykinin under physiological conditions. The present study sought to investigate whether the B(2)R gene deletion will have an impact on myocardial function.

Main Methods: Isolated cell shortening, patch-clamp technique, Western blot and confocal microscopy.

Key Findings: Isolated cell shortening measurements showed significant reduction in B(2)R knockout (B(2)R(-/-)) left ventricular cardiac myocytes' shortening. Whole-cell recordings were used to study the electrophysiological aspects of the left ventricular B(2)R(-/-) cardiomyocytes. Results showed: 1) action potential lengthening; 2) unchanged inwardly rectifying K(+) current; 3) reduced transient outward K(+) (I(to)) and L-type Ca(2+) current densities; 5) changes in kinetic properties related to I(to) and I(Ca,L). In addition, transient sarcoplasmic reticulum (SR) Ca(2+) release was found to be smaller in B(2)R(-/-) cardiomyocytes. Importantly, evidence is provided that NO constitutive production is, at least in part, responsible for the reported electrophysiological modifications observed in cardiomyocytes from B(2)R(-/-) mice. Surprisingly, NO is not involved in the SR Ca(2+) release reduction as demonstrated in the present study.

Significance: Taken together, our findings indicate that B(2)R plays a fundamental role in the regulation of cardiac function and Ca(2+) homeostasis, probably through a NO dependent pathway. These results may contribute to our understanding of the kinins participation in the control of cardiac function.
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http://dx.doi.org/10.1016/j.lfs.2010.10.011DOI Listing
December 2010

Cardiotoxic effects of Loxosceles intermedia spider venom and the recombinant venom toxin rLiD1.

Toxicon 2010 Dec 6;56(8):1426-35. Epub 2010 Sep 6.

Biochemistry Departament, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, CP: 486, CEP: 30161-970, Belo Horizonte, Brazil.

Loxosceles spider bites cause many human injuries worldwide. Injections in mice of whole Loxosceles (L.) intermedia venom or a recombinant toxin (rLiD1) produce systemic symptoms similar to those detected in envenomed humans. This animal model was used to characterize the effects of Loxosceles intermedia venom in cardiac tissues. L. intermedia antigens were detected by ELISA in kidney, heart, lung and liver of experimentally envenomed mice. In addition, rLiD1 binding to cardiomyocytes was demonstrated by immunofluorescence and confocal microscopy. Furthermore, isolated perfused heart preparations and ventricular cardiomyocytes from envenomed mice showed heart function impairment, and a significant increase of I(Ca,L) density and intracellular Ca(2+) transients, respectively. Thus, L. intermedia spider venom, as shown through the use of the recombinant toxin rLiD1, causes cardiotoxic effects and a protein from the sphingomyelinase D family plays a key role in heart dysfunction. Thus, L. intermedia spider venom and the Loxtox rLiD1 play a key role in heart dysfunction.
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http://dx.doi.org/10.1016/j.toxicon.2010.08.008DOI Listing
December 2010

Morphine peripheral analgesia depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway.

Proc Natl Acad Sci U S A 2010 Mar 10;107(9):4442-7. Epub 2010 Feb 10.

Department of Pharmacology, Faculty of Medicine, Ribeirão Preto University of São Paulo, Ribeirão Preto, 14049-900 São Paulo, Brazil.

Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3Kgamma/AKT protein kinase B (AKT) and culminated in increased activation of K(ATP) channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.
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http://dx.doi.org/10.1073/pnas.0914733107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840166PMC
March 2010

Hereditary gastrointestinal stromal tumors sharing the KIT Exon 17 germline mutation p.Asp820Tyr develop through different cytogenetic progression pathways.

Genes Chromosomes Cancer 2010 Feb;49(2):91-8

Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.

Hereditary gastrointestinal stromal tumor (GIST) syndrome is a rare autosomal dominant genetic disorder originated by germline mutations in the KIT or PDGFRA genes. We report the third family with hereditary predisposition to GIST due to the KIT Exon 17 germline mutation p.Asp820Tyr and characterize the cytogenetic progression pathways followed by different GIST sharing the same primary genetic event, using a combination of chromosome banding, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH) analyses. The missense mutation p.Asp820Tyr was detected in the proband's rectal and gastric GIST, as well as in his aunt's GIST epiplon metastasis. The mutation p.Asp820Tyr was subsequently also found in the proband's peripheral blood DNA, as well as in that of 4 of 10 relatives thus far analyzed. CGH analysis revealed loss of 14q and 15q in the proband's gastric lesion, whereas FISH analysis of the proband's rectal GIST did not detect loss of 14q and 15q, but instead loss of 4q and 22q and gain of 20q, indicating that the two tumors were independent GIST. Chromosome banding and CGH analyses of the aunt's GIST epiplon metastasis revealed multiple cytogenetic alterations, including 1p loss, but none in common with the two proband's GIST. We conclude that, although the patients share the same KIT Exon 17 germline mutation, the multiple GIST analyzed followed different pathogenetic progression pathways, each of which did not significantly differ from what has been described in sporadic GIST.
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http://dx.doi.org/10.1002/gcc.20720DOI Listing
February 2010

Changes in cellular contractility and cytokines profile during Trypanosoma cruzi infection in mice.

Basic Res Cardiol 2009 May 3;104(3):238-46. Epub 2009 Feb 3.

Dept. of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Trypanosoma cruzi, an intracellular protozoan parasite infecting a wide variety of vertebrates, is the agent responsible for Chagas' disease. This pathology often results in severe inflammatory heart condition and it is one of the major causes of dilated cardiomyopathy leading to heart failure in Latin America. Nevertheless, little is known about the changes in isolate cardiac myocytes contractility during the development of this pathology. Here we report a relationship between cytokines profile of mice infected with T. cruzi and the modifications in the cellular contractility pattern. We found that cellular contractility, measured as fractional shortening, showed a complex behavior. The changes were evaluated during the acute phase (15, 30 and 45 dpi) and chronic phase (>90 dpi). The time to half contraction and relaxation were lengthier despite the number of days after infection or the heart region evaluated. The maximal contraction and relaxation velocities were significantly slower. The observed changes in cellular contractility were correlated with the presence of circulating IFN-gamma, TNF-alpha and MCP-1/CCL2 during the course of infection. Together, our data demonstrate that cellular contractility is altered in the three heart regions studied, and these alterations are observed at the very beginning of the parasitism and they remained until the chronic phase has been reached. Indeed, we propose a role for IFN-gamma, TNF-alpha and MCP-1/CCL2 in the mechanical heart remodeling during experimental Chagas' disease.
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http://dx.doi.org/10.1007/s00395-009-0776-xDOI Listing
May 2009

Value of SPET/CT image fusion in the assessment of neuroendocrine tumours with 111In-pentetreotide scintigraphy.

Rev Esp Med Nucl 2005 Jan-Feb;24(1):14-8

Serviço de Medicina Nuclear, Hospitais da Universidade de Coimbra, Portugal.

Objective: The purpose of this study was to evaluate the impact and clinical value of anatomical-functional image fusion in the study interpretation and clinical management of patients with neuroendocrine tumours (NET) using somatostatin receptor scintigraphy (SRS) and combined transmission and emission tomography -- single-photon emission tomography/CT (SPET/CT).

Material And Methods: Twelve patients (8 female and 4 male; age range 32-74 y, mean 56 y) with proven or clinically suspected NET were studied with routine planar SRS and SPET/CT at 2 and 24 hours after injection of 111-222 MBq 111In-Pentetreotide. Seven patients came for staging/follow-up and 5 patients for primary tumour localization with staging. Analysis of fused images (SPET/CT) was done on a patient basis, with separated evaluation of SPET, low-dose CT images and fusion images. The gold standard for presence or absence of malignancy was pathology or clinical and imaging follow-up data.

Results: SRS was negative in 6 patients and positive in 6. SPET/CT provided no additional information in 6 patients, including all 6 negative studies. SPET/CT improved localization of SPET detected lesions in 6 positive studies. It defined the extent of the disease and showed bone involvement in 3 of the 6 positive studies. SPET/CT affected the diagnostic interpretation in 6 patients (50 %) and induced changes of management in 3 (25 %).

Conclusion: The results of this study indicate that combined anatomical-functional imaging with SPET/CT significantly improves tumour localization and characterization, contributing to a better therapeutic management of patients with NET.
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http://dx.doi.org/10.1157/13070352DOI Listing
July 2005
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