Publications by authors named "Isabel Azevedo"

85 Publications

Linear scleroderma en coup de sabre - a different clinical presentation.

Acta Reumatol Port 2021 Jan-Mar;46(1):72-76

Centro Hospitalar Universitário Cova da Beira.

Localized scleroderma (LoS) is a rare condition featuring skin and underlying tissue sclerosis not usually compromising other systems. A subtype of LoS including lesions in the head is further classified as linear scleroderma en coup de sabre (LSeCS). Neurological involvement in LSeCS can reach up to 4% and may include seizures. Cutaneous lesions usually emerge before neurologic symptoms and these oftentimes manifest with intracranial abnormalities. We describe a case of an 11-year-old boy with an onset of self-limited unexplained seizures at 20-months of life. During the first year of follow-up, a midline frontoparietal lesion with alopecia and hypopigmentation was noted and a referral to dermatology and pediatric rheumatology consultation was made. A diagnosis of LEsCS was made. A 10-year follow-up of this patient is presented with favorable outcome. LSeCS is a rare form of LoS most frequently diagnosed in children and adolescents. A meticulous examination of these patients should be performed with particular attention to the face and scalp. The mainstay therapeutical approach is based on methotrexate and corticosteroids. Neurologic abnormalities associated with skin lesions on the head should should raise clinical suspicion of LSeCS.
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November 2021

Real-World T790M Mutation Frequency and Impact of Rebiopsy in Patients With EGFR-Mutated Advanced Non-Small Cell Lung Cancer.

Cureus 2020 Dec 17;12(12):e12128. Epub 2020 Dec 17.

Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Porto, PRT.

Introduction The T790M resistance mutation is present in about one-half of epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) patients at disease progression. We aimed to assess the prevalence of this mutation in a real-world setting and the clinical impact of repeated biopsies in its detection. Methods This was a single-center retrospective cohort study of patients with EGFR-positive advanced NSCLC diagnosed between 2016 and 2018, who experienced radiographic disease progression during first-line treatment with first- or second-generation EGFR-tyrosine kinase inhibitor (TKI). The frequency of T790M detection and the number of rebiopsies were determined. Results A total of 88 patients were included, with a median age of 65 years (range: 38-84 years). The majority of the participants were females (63 (72%)) and non-smokers (70 (81%)). Upon disease progression, 80 (91%) patients were tested for T790M mutation, and the resistance mutation was detected in 57 (71%) cases (58% in plasma samples and 42% in tissue/cytology samples). In 14 (25%) cases, T790M mutation was only detected after rebiopsy (57% by liquid biopsy), which increased the rate of mutation detection in 17%. Subsequent treatment with third-generation EGFR-TKI was possible in 42 (74%) of T790M-positive cases. Detection of T790M mutation was more likely in patients who were less than 65 years old, with EGFR exon 19 deletions and duration of first-line treatment of more than 12 months (p < 0.05). Conclusions The frequency of T790M mutation in this study was higher than previously reported, suggesting that repeated biopsies after a negative result are beneficial. This allowed a greater percentage of patients to receive sequential osimertinib in our clinical practice.
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http://dx.doi.org/10.7759/cureus.12128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810175PMC
December 2020

Actinobacteria Isolated From : A Source of New Bioactive Compounds.

Front Microbiol 2019 9;10:683. Epub 2019 Apr 9.

Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Porto, Portugal.

Nature is the major reservoir of biologically active molecules. The urgent need of finding novel molecules for pharmaceutical application is prompting the research of underexplored environments, such as marine ecosystems. Here, we investigated cultivable actinobacteria associated with the macroalgae and assessed their potential to produce compounds with antimicrobial or anticancer activities. A specimen of was collected in a rocky shore in northern Portugal, and fragments of tissues from different parts of the macroalgae (holdfast, stipe, and blades) were surface sterilized and plated in three culture media selective for actinobacteria. A total of 90 actinobacterial strains were isolated, most of which affiliated with the genus . Isolates associated with the genera , , , , , and were also obtained. Organic extracts from the isolates were tested for their antimicrobial activity using the agar-based disk diffusion method, followed by determination of minimum inhibitory concentration (MIC) values. Forty-five isolates inhibited the growth of and/or , with MIC values ranging from <0.5 to 1000 μg mL. The actinobacterial isolates were also tested for their anticancer potential on two human cancer cell lines. Twenty-eight extracts affected the viability of at least one human cancer cell line (breast carcinoma T-47D and neuroblastoma SH-SY5Y) and non-carcinogenic endothelial cell line (hCMEC/D3). Seven extracts affected the viability of cancer cells only. This study revealed that is a rich source of actinobacteria with promising antimicrobial and anticancer activities and suggests that macroalgae may be a valuable source of actinobacteria and, consequently, of new molecules with biotechnological importance.
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http://dx.doi.org/10.3389/fmicb.2019.00683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465344PMC
April 2019

Chemical profiling of edible seaweed (Ochrophyta) extracts and assessment of their in vitro effects on cell-free enzyme systems and on the viability of glutamate-injured SH-SY5Y cells.

Food Chem Toxicol 2018 Jun 17;116(Pt B):196-206. Epub 2018 Apr 17.

REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n.º 228, Porto 4050-313, Portugal. Electronic address:

Neurodegenerative processes involve numerous and closely related events that ultimately culminate in neuronal cell injury. The aim of this study was (i) to assess, for the first time, the neuroprotective potential of acetone extracts of six edible species of Ochrophyta, by evaluating their cholinesterase and lipoxygenase inhibitory activity in cell-free assays, as well as their capacity to attenuate glutamate-induced toxicity in neuronal (SH-SY5Y) cells, and (ii) to try to relate the chemical composition of the extracts with their biological activity, evaluating also the effect of the main compounds thereof. In spite of a modest cholinesterase inhibition, a dose-dependent response towards lipoxygenase was found for all macroalgae extracts. At non-cytotoxic concentrations, the extracts from Fucus serratus Linnaeus and Saccharina latissima (Linnaeus) C.E. Lane, C. Mayes, Druehl & G.W. Saunders were able to improve the viability of glutamate-insulted SH-SY5Y cells. These results encourage further studies for a more detailed understanding of the mechanisms beyond the documented biological activities, and point to the potential interest of the selected seaweed species and their extracts as promising candidates for in vivo studies.
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http://dx.doi.org/10.1016/j.fct.2018.04.033DOI Listing
June 2018

[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

Differential effects of crude oil on denitrification and anammox, and the impact on N2O production.

Environ Pollut 2016 Sep 7;216:391-399. Epub 2016 Jul 7.

CIMAR/CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Rua dos Bragas, 289, 4050-123 Porto, Portugal.

Denitrification and anammox are key processes for reducing the external nitrogen loads delivered to coastal ecosystems, and these processes can be affected by pollutants. In this study, we investigated the effect of crude oil on denitrification and anammox. Controlled laboratory experiments were performed using sediment slurries from the Lima Estuary (NW Portugal). Anammox and denitrification rates were measured using (15)N-labeled NO3(-), and the production of (29)N2 and (30)N2 quantified by membrane inlet mass spectrometry. Results revealed that while denitrification rates were stimulated between 10 and 25 000 times after crude oil amendment, anammox activity was partially (between 2 and 5 times) or completely inhibited by the addition of crude oil when comparing to rates in unamended controls. Similar results were observed across four estuarine sediment types, despite their different physical-chemical characteristics. Moreover, N2O production was reduced by 2-36 times following crude oil addition. Further work is required to fully understand the mechanism(s) of the observed reduction in N2O production. This study represents one of the first contributions to the understanding of the impact of crude oil pollution on denitrification and anammox, with profound implications for the management of aquatic ecosystems regarding eutrophication (N-removal).
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http://dx.doi.org/10.1016/j.envpol.2016.05.045DOI Listing
September 2016

Effect of a natural mineral-rich water on catechol-O-methyltransferase function.

Magnes Res 2014 Jul-Sep;27(3):131-41

Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal, Department of Education and Medical Simulation, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

Catechol-O-methyltransferase (COMT) is a magnesium-dependent, catecholamine-metabolizing enzyme, whose impaired activity has been positively associated with cardiovascular diseases, particularly hypertension. Consumption of some natural mineral-rich waters has been shown to exert protective effects on cardiovascular risk factors, eg. by decreasing arterial blood pressure and blood lipids. However, the molecular mechanisms underlying these effects are still poorly understood. So, the aim of this work was to investigate the effect of natural mineral-rich water ingestion upon liver and adrenal glands COMT expression and activity in Wistar Han rats. Over a seven-week period, animals had access to one of the following three drinking solutions: 1) tap water (control group; TW), 2) tap water with added Na(+) (to make the same concentration as in the MW group (TWNaCl group), or 3) natural mineral-rich water [Pedras Salgadas(®), which is very rich in bicarbonate, and with higher sodium, calcium and magnesium content than control tap water (MW group)]. COMT expression and activity were determined by RT-PCR and HPLC-ED, respectively. A higher hepatic COMT activity was found in the MW group compared with the TW and TWNaCl groups. On the other hand, adrenal gland COMT mRNA expression decreased in the MW group compared to TW group. In conclusion, the ability of natural mineral-rich waters to increase hepatic COMT activity may eventually explain the positive cardiovascular effects associated with the consumption of some natural mineral-rich waters.
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http://dx.doi.org/10.1684/mrh.2014.0369DOI Listing
July 2015

Evaluation of axillary dose coverage following whole breast radiotherapy: variation with the breast volume and shape.

Radiother Oncol 2015 Jan 4;114(1):22-7. Epub 2014 Nov 4.

Serviço de Física Médica, Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E., Portugal.

Objective: To evaluate the axillary dose coverage in patients treated with tridimensional whole breast radiotherapy (3D-WBRT), according to the breast volume and shape in treatment position.

Background: Several studies have demonstrated an insufficient dose contribution to the axillary levels, using 3D-WBRT, remaining unclear whether the breast volume and shape can influence it.

Materials And Methods: We retrospectively delineated the axillary levels on planning CT-images of 100 patients, treated with 3D-WBRT along 2012 in our institution. To estimate the shape we established an anatomic CT-based interval, defined as the Thoracic Extent (TE). The breast volume matched its CTV. Mean dose levels and V95 (volume receiving at least 95% of the prescribed dose) were evaluated.

Results: Mean axillary level I (A1), II (A2) and III (A3) volume was 56.1 cc, 16.5 cc and 18.9 cc, respectively, and mean doses were 43.9 Gy, 38.6 Gy and 19.5 Gy. For breast volumes of <800 cc, 800-999 cc, 1000-1199 cc and >1200 cc, mean A1 V95 was 38%, 51%, 61.2% and 57.2% whereas median A2 V95 was 8.3%, 13.4%, 19.4% and 28% respectively. Regarding shape, where the breast relative position to the TE was categorized in intervals between 31% and 40%, 41% and 50%, 51% and 60%, and 61% and 70%, mean A1 V95 was 38.7%, 43.1%, 51.1% and 77.3% whereas mean A2 V95 was 6.1%, 11.2%, 17.1% and 37% respectively.

Conclusions: We observed inadequate dose coverage to all axillary levels, even after applying a sub-analysis accounting for different breast volumes and shapes. Although higher doses were associated with the more voluminous and pendulous breasts, axillary coverage with 3D-WBRT seems to be inefficient, regardless of the breast morphology.
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http://dx.doi.org/10.1016/j.radonc.2014.10.005DOI Listing
January 2015

Breast cancer local recurrence under the form of inflammatory carcinoma, treated with concurrent radiation and chemotherapy, a case report.

Rep Pract Oncol Radiother 2014 Jan 20;19(1):65-8. Epub 2013 Oct 20.

Oncology Department, Instituto Português de Oncologia Francisco Gentil do Porto, E.P.E., Porto, Portugal.

The authors present a case report of a patient with breast cancer diagnosed in 2005, treated with conservative surgery, adjuvant chemotherapy and radiotherapy, followed by hormonal therapy until 2010, who relapsed under the form of inflammatory breast cancer in 2011. After tumor progression detected during primary systemic therapy, a concurrent radiation and radiosensitizing chemotherapy were proposed. There was a significant clinical response to this treatment, enabling curative chance with total mastectomy. The histological examination of the breast and regional lymph nodes revealed a complete response, since there was no evidence of residual tumor. There are few reports concerning concurrent radiotherapy and chemotherapy in locally advanced breast cancer, but it could be a suitable "loco regional rescue therapy" to further reduce tumor progression and allow curative surgery. Study of this treatment strategy in randomized clinical trials is warranted.
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http://dx.doi.org/10.1016/j.rpor.2013.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056521PMC
January 2014

Relevance of a Hypersaline Sodium-Rich Naturally Sparkling Mineral Water to the Protection against Metabolic Syndrome Induction in Fructose-Fed Sprague-Dawley Rats: A Biochemical, Metabolic, and Redox Approach.

Int J Endocrinol 2014 5;2014:384583. Epub 2014 Feb 5.

Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

The Metabolic Syndrome increases the risk for atherosclerotic cardiovascular disease and type 2 Diabetes Mellitus. Increased fructose consumption and/or mineral deficiency have been associated with Metabolic Syndrome development. This study aimed to investigate the effects of 8 weeks consumption of a hypersaline sodium-rich naturally sparkling mineral water on 10% fructose-fed Sprague-Dawley rats (Metabolic Syndrome animal model). The ingestion of the mineral water (rich in sodium bicarbonate and with higher potassium, calcium, and magnesium content than the tap water used as control) reduced/prevented not only the fructose-induced increase of heart rate, plasma triacylglycerols, insulin and leptin levels, hepatic catalase activity, and organ weight to body weight ratios (for liver and both kidneys) but also the decrease of hepatic glutathione peroxidase activity and oxidized glutathione content. This mineral-rich water seems to have potential to prevent Metabolic Syndrome induction by fructose. We hypothesize that its regular intake in the context of modern diets, which have a general acidic character interfering with mineral homeostasis and are poor in micronutrients, namely potassium, calcium, and magnesium, could add surplus value and attenuate imbalances, thus contributing to metabolic and redox health and, consequently, decreasing the risk for atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.1155/2014/384583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941211PMC
March 2014

Comment to: Luo et al. (2013) Int J Cardiol. 168(4):4454-6.

Int J Cardiol 2014 Mar 23;172(2):512-4. Epub 2014 Jan 23.

Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2014.01.044DOI Listing
March 2014

Lobular ectopic breast carcinoma: A case-report.

Rep Pract Oncol Radiother 2013 18;18(3):189-91. Epub 2013 Apr 18.

Radiotherapy Department, Instituto Português de Oncologia Francisco Gentil do Porto, E.P.E., Portugal.

In about 1-2% of the population an incomplete regression of the embryonic mammary line occurs, which may result in the presence of ectopic breast tissue. An ectopic breast tissue carcinoma is a rare entity. The authors present a case-report of a 51-year-old female patient, with a lobular carcinoma in an axillary ectopic breast tissue submitted to surgery and adjuvant radiotherapy.
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http://dx.doi.org/10.1016/j.rpor.2013.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863212PMC
January 2014

Effects of raftilose on serum biochemistry and liver morphology in rats fed with normal or high-fat diet.

Mol Nutr Food Res 2013 Aug 8;57(8):1468-72. Epub 2013 May 8.

Institute of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.

Non-alcoholic fatty liver disease is the leading cause of chronic liver injury in developed countries. Oligofructose (OFS) is a prebiotic with proven benefits for health. The aim of the study is to evaluate the effect of 10% OFS on hepatic morphology and lipid metabolism in Wistar Kyoto rats submitted to normal diet (ND) or high-fat diet (FD). Animals were treated for 7 weeks. Lipid profile and serum alkaline phosphatase (ALP) activity were measured and liver histology evaluated at the end of the study. Ten percent OFS reduced triglyceride (TAG) levels when added to any of the diet regimens; 10% OFS decreased plasmatic urea in ND and plasmatic and urinary urea levels in FD; ND + 10% OFS treated rats showed lower ALP activity than controls. FD increased ALP activity, an effect not reversed by OFS. Animals submitted to FD have microscopic hepatic changes: marked steatosis with disarranged centrilobular zone structure; enlarged sinusoids; enlarged mitochondria and an increase in number and volume of adiposomes. Supplementation with 10% OFS in FD reversed those effects. In conclusion, 10% OFS supplementation prevented deleterious effects of FD such as alterations on lipid profile (TAG elevation) and hepatic morphologic changes. OFS decreased ALP activity in animals subjected to ND, which may have contributed to the differences on lipid metabolism.
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http://dx.doi.org/10.1002/mnfr.201200693DOI Listing
August 2013

EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study.

Tumour Biol 2012 Dec 29;33(6):2061-8. Epub 2012 Jul 29.

Department of Medical Oncology, Portuguese Oncology Institute, Rua Dr António Bernardino de Almeida, 4200-079 Porto, Portugal.

Epidermal growth factor receptor (EGFR) mutations play a predictive role in advanced stages of non-small-cell lung cancer (NSCLC) patients. We conducted this study in order to assess EGFR status in a Portuguese population and its role in NSCLC patients' outcomes. Patients were submitted to EGFR assessment by high-resolution melting and/or direct sequencing. Kaplan-Meier curve was used to assess overall survival and progression-free survival (PFS). Two hundred forty eight out of 322 participants were assessed for EGFR status. Forty-two patients (16.9 %) presented EGFR-mutated status: one patient (2.4 %) presented exon 18; 21 patients (50 %), exon 19; one patient (2.4 %), exon 20; and 18 patients (45.2 %), exon 21 mutations, p < 0.001. PFS was not assessed (n.a.) for patient with exon 18 mutation, and for the other patients with mutations, it was 7 months (3.96-10.03) (exon 19), <1 month (exon 20), and 7 months (0-14.2) (exon 21) (p = 0.027). Overall survival (OS) was 11 months (exon 18), 11 months (1-18) (exon 19), 1 month (exon 20), and 7.5 months (2-70) (exon 21) (p = n.a). This study suggests that the EGFR mutation is herein observed in a higher proportion than expected for a Caucasian population, and OS is a little less than that published in the literature.
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http://dx.doi.org/10.1007/s13277-012-0465-5DOI Listing
December 2012

Different effects of catechin on angiogenesis and inflammation depending on VEGF levels.

J Nutr Biochem 2013 Feb 15;24(2):435-44. Epub 2012 Jun 15.

Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.

Although physiological and pathological angiogenesis develop through similar processes, during pathological angiogenesis, proangiogenic factors are exacerbated. Polyphenols have been considered therapeutic tools for conditions exhibiting enhanced angiogenesis. However, the possibility that these compounds may also prevent vascularization in physiological situations is a major drawback for their use. The purpose of the current study was to investigate the effects of 0.1-100 μM catechin on endothelial cells (EC) and vascular smooth muscle cells (VSMC) regarding angiogenic and inflammatory processes. Catechin modulation of angiogenesis and inflammation was also evaluated in vivo using different models of angiogenesis: one physiological (skin wound-healing assay) and another one resembling pathological angiogenesis, exhibiting higher vascular endothelial growth factor (VEGF)-A stimulation (Matrigel plug assay). The in vitro results showed that 100 μM catechin increased viability (to 165.58% and to 165.34%) and decreased apoptosis (53.45% and 92.65%) and proliferation (33.19% and 23.36%) of EC and VSMC, respectively. Catechin affected migration and invasion, tending to increase both in EC and decreasing them in VSMC; however, it did not change sprouting angiogenesis. Nevertheless, catechin diminished in vitro inflammatory modulators such as tumor necrosis factor α (58.66% for human umbilical vein endothelial cells and 85.46% for human aortic smooth muscle cells) and nuclear factor kappa-B (38.43% for VSMC). The in vivo results demonstrated that catechin did not change angiogenesis and inflammation in skin wound-healing model and substantially decreased these processes in Matrigel plug assay. Altogether, the current study showed that catechin has different effects in angiogenesis and inflammation depending on VEGF-A levels. The absence of adverse effects in mature vasculature favors catechin potential use against pathological situations where angiogenesis is stimulated.
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http://dx.doi.org/10.1016/j.jnutbio.2011.12.011DOI Listing
February 2013

Bevacizumab for the treatment of nonsquamous non-small-cell lung cancer in Portugal: a retrospective, multicenter study.

Cancer Manag Res 2012 13;4:91-7. Epub 2012 Mar 13.

Medical Oncology Resident, Department of Medical Oncology, Portuguese Institute of Oncology, Oporto Center, Oporto, Portugal.

Introduction: Lung cancer is the leading cause of cancer-related mortality. In patients with nonsquamous non-small-cell lung cancer (NSCLC) stage IIIB/IV treatment with chemotherapy plus bevacizumab led to significant improvements in progression-free and median overall survival (OS).

Aim: To report the experience of five Portuguese centers in treating patients with nonsquamous NSCLC in stage IIIB or IV with bevacizumab and chemotherapy regarding survival and toxicity outcomes.

Materials And Methods: This was a retrospective, multicenter study on patients with nonsquamous stage IIIB/IV NSCLC treated with bevacizumab and chemotherapy from November 2007 to August 2010 through special use permits. We reviewed the medical records, registry of demographic characteristics, treatments provided, treatment responses, adverse events, and dates of death. Statistical analysis was performed with SPSS statistics software. Median OS and event-free survival (EFS) were calculated using the Kaplan-Meier method.

Results: From an eligible population of 41 patients, 37 participants were registered. Study participants were predominantly male (78.4%) with a median age of 53 years (29-75 years). In total, 83.8% patients had stage IV disease (TNM, 6th Ed.). The OS was 21.5 months (95% confidence interval [CI]: 12.6-30.5] and median EFS was 9.4 months (95% CI9: 7.1-11.7). Hematologic toxicity grade 3/4 occurred in 35.1% of patients, and nonhematologic toxicity in 24.3% patients. One fatal thromboembolic event was recorded (2.7%).

Conclusions: The results of chemotherapy plus bevacizumab treatment for nonsquamous NSCLC obtained from the daily clinical practice of the centers involved in this study were similar to those of published clinical trials. Collaboration between the different Portuguese centers is crucial for this kind of study.
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http://dx.doi.org/10.2147/CMAR.S29672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308635PMC
October 2012

Xanthohumol-supplemented beer modulates angiogenesis and inflammation in a skin wound healing model. Involvement of local adipocytes.

J Cell Biochem 2012 Jan;113(1):100-9

Department of Biochemistry (U38-FCT), University of Porto, Porto 4200-319, Portugal.

Angiogenesis and inflammation are two intermingled processes that play a role in wound healing. Nevertheless, whenever exacerbated, these processes result in nonhealing wounds. Xanthohumol (XN), a beer-derived polyphenol, inhibits these processes in many physiopathological situations. This study aimed at examining whether XN ingestion affects wound healing. Wistar rats drinking water, 5% ethanol, stout beer (SB) or stout beer supplemented with 10 mg/L XN (Suppl SB) for 4 weeks, were subjected to a 1.5 cm full skin-thickness longitudinal incision, and further maintained under the same beverage conditions for another week. No differences in beverage consumption or body weight were found throughout the study but food intake decreased in every group relative to controls. Consumption of Suppl SB resulted in decreased serum VEGF levels (18.42%), N-acetylglucosaminidase activity (27.77%), IL1β concentration (9.07%), and NO released (77.06%), accompanied by a reduced redox state as observed by increased GSH/GSSG ratio (to 198.80%). Also, the number of blood vessels within the wound granulation tissue seems to reduce in animals drinking Suppl SB (23.08%). Interestingly, SB and primarily Suppl SB showed a tendency to increase adipocyte number (to 194.26% and 156.68%, respectively) and reduce adipocyte size (4.60% and 24.64%, respectively) within the granuloma. Liver function and metabolism did not change among the animal groups as analyzed by plasma biochemical parameters, indicating no beverage toxicity. This study shows that XN intake in its natural beer context reduced inflammation, oxidative stress, and angiogenesis, ameliorating the wound healing process, suggesting that this polyphenol may exert beneficial effect as a nutritional supplement.
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http://dx.doi.org/10.1002/jcb.23332DOI Listing
January 2012

Angiogenesis and inflammation signaling are targets of beer polyphenols on vascular cells.

J Cell Biochem 2010 Dec;111(5):1270-9

Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

Emerging evidence indicates that chronic inflammation and oxidative stress cluster together with angiogenic imbalance in a wide range of pathologies. In general, natural polyphenols present health-protective properties, which are likely attributed to their effect on oxidative stress and inflammation. Hops used in beer production are a source of polyphenols such as xanthohumol (XN), and its metabolites isoxanthohumol (IXN) and phytoestrogen 8-prenylnaringenin (8PN). Our study aimed to evaluate XN, IXN, and 8PN effects on angiogenesis and inflammation processes. Opposite in vitro effects were observed between 8PN, stimulating endothelial and smooth muscle cell (SMC) growth, motility, invasion and capillary-like structures formation, and XN and IXN, which inhibited them. Mouse matrigel plug and rat skin wound-healing assays confirmed that XN and IXN treatments reduced vessel number as well as serum macrophage enzymatic activity, whereas 8PN increased blood vessels formation in both assays and enzyme activity in the wound-healing assay. A similar profile was found for serum inflammatory interleukin-1β quantification, in the wound-healing assay. Our data indicate that whereas 8PN stimulates angiogenesis, XN and IXN manifested anti-angiogenic and anti-inflammatory effects in identical conditions. These findings suggest that the effects observed for individual compounds on vascular wall cells must be carefully taken into account, as these polyphenols are metabolized after in vivo administration. The modulation of SMC proliferation and migration is also of special relevance, given the role of these cells in many pathological conditions. Furthermore, these results may provide clues for developing useful therapeutic agents against inflammation- and angiogenesis-associated pathologies.
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http://dx.doi.org/10.1002/jcb.22850DOI Listing
December 2010

Intestinal oxidative state can alter nutrient and drug bioavailability.

Oxid Med Cell Longev 2009 Nov-Dec;2(5):322-7

University of Porto, Porto, Portugal.

Organic cations (OCs) are substances of endogenous (e.g. dopamine, choline) or exogenous (e.g. drugs like cimetidine) origin that are positively charged at physiological pH. Since many of these compounds can not pass the cell membrane freely, their transport in our out of cells must be mediated by specific transport systems. Transport by organic cation transporters (OCTs) can be regulated rapidly by altering their trafficking and/or affinities in response to a stimuli. However, for example, a specific disease could lead to modifications in the expression of OCTs. Chronic exposure to oxidative stress has been suggested to alter regulation and functional activity of proteins through several pathways. According to results from a previous work, oxidation-reduction pathways were thought to be involved in intestinal organic cation uptake modulation. The present work was performed in order to evaluate the influence of oxidative stressors, especially glutathione, on the intestinal organic cation absorption. For this purpose, the effect of compounds with different redox potential (glutathione, an endogenous antioxidant, and procyanidins, diet antioxidants) was assessed on MPP+ (1-methyl-4-phenylpyridinium iodide) uptake in an enterocyte cell line (Caco-2). Caco-2 cells were subcultured with two different media conditions (physiological: 5 mM glucose, referred as control cells; and high-glucose: 25 mM glucose, referred as HG cells). In HG cells, the uptake was significantly lower than in control cells. Redox changing interventions affected MPP+ uptake, both in control and in high-glucose Caco-2 cells. Cellular glutathione levels could have an important impact on membrane transporters activity. The results indicate that modifications in the cellular oxidative state modulate MPP+ uptake by Caco-2 cells. Such modifications may reflect in changes of nutrient and drug bioavailability.
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http://dx.doi.org/10.4161/oxim.2.5.9769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835921PMC
January 2011

Chronic inflammation in obesity and the metabolic syndrome.

Mediators Inflamm 2010 14;2010. Epub 2010 Jul 14.

Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.

The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.
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http://dx.doi.org/10.1155/2010/289645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913796PMC
November 2010

[Sugary drinks and glycemia].

Acta Med Port 2010 Jul-Aug;23(4):567-78. Epub 2010 Jul 30.

Departamento de Bioquímica (U38-FCT), Faculdade de Medicina da Universidade do Porto, Porto.

Obesity prevalence is increasing all over the world. Most affected are people changing from a traditional lifestyle to an environment with both availability of high energy diet and less physical activity. Glycemic index (GI) is a measure of dietary glycemic carbohydrates, representing their ability to raise blood glucose concentrations. It refers to the postprandial blood glucose response expressed as a percentage of the response to a reference food (glucose or white bread) containing the same carbohydrate content. Given the present high consumption of sugary drinks, the putative contribution of these products to obesity deserves investigation. The aim of this study was to determine the GI of some drinks from the Portuguese market. Postprandial glycemia after ingestion of apple Frutis, peach Frutis, Green tea Frutea, green tea, black tea, lupin infusion, rooibos infusion, raftilose solution or bran solution has been determined for two hours in a caucasian population of young adults of any sex, 17 to 24 years of age. Apple Frutis GI was found to be 54.3, i.e., a low GI; Frutea Green tea had a GI of 64.7, considered as a moderate GI; peach Frutis showed a high GI, 86.6. Green and Black teas as well as rooibos and lupin infusions, all with added glucose (25 g), did not change glycemic response in comparison with the reference solution (water with 25 g glucose). No differences were seen after raftilose and bran solutions by comparison with the reference solution. GI information may help the choice of carbohydrates to include in a healthy diet. Formerly considered as a parameter of interest to diabetic patients, it may actually interest anybody concerned with a healthy diet. This study has been performed by medical and nutritional science students, who observed glycemic excursions in themselves, after drink ingestion. This experiment allowed them to see the impressive rise of glycemia after ingestion of a sugary drink, by comparison with basal levels which would not rise if plain water or other nonsugary drink had been ingested.
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November 2010

Epstein-Barr virus detection in nasopharyngeal carcinoma: implications in a low-risk area.

Braz J Otorhinolaryngol 2010 May-Jun;76(3):310-5

Instituto Português de Oncologia Francisco Gentil do Porto, EPE, Portugal.

Unlabelled: Several studies have been published concerning Epstein-barr virus (EBV) infection and nasopharyngeal cancer (NPC) development. The incidences of histological types are different according to endemic or non-endemic regions. Latent EBV infection is found in almost all cases of NPC in endemic regions, but normally absent in type I carcinomas, more common in non-endemic regions.

Aim: The purpose of this hospital-based study was to analyze the presence of EBV in nasopharyngeal tumor tissues and in peripheral blood of nasopharyngeal cancer patients and healthy individuals, in a low risk, non-endemic area.

Methods: EBV detection in samples of nasopharyngeal cancer patients and healthy individuals.

Results: This study indicates that the frequency of EBV positive cases in peripheral blood is higher in advanced tumor stages.

Conclusions: The incidence rates of NPC have a distinct distribution. Since the prevalence of this disease is low in occidental countries, little is known about the biology of these tumors in non-endemic areas. We observed statistically significant differences in EBV detection between the NPC patient group and the control group. This study may help to understand the biological mechanisms of NPC and the correlation of EBV infection with this disease, in a low risk, non-endemic region.
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January 2011

Sodium-rich carbonated natural mineral water ingestion and blood pressure.

Rev Port Cardiol 2010 Feb;29(2):159-72

Serviço de Bioquímica (U38/FCT), Faculdade de Medicina, Universidade do Porto, Porto, Portugal.

Introduction: There is a strong positive correlation between sodium chloride intake and hypertension. In industrialized countries the ingestion of carbonated and non-carbonated mineral water is an important source of calorie-free fluids. The mineral content of these waters varies greatly, with many brands containing high levels of sodium. However, some mineral waters contain greater amounts of bicarbonate instead of chloride as the anion associated with the sodium cation. This is relevant because it is well established that the effect of sodium on blood pressure depends on the corresponding anion. Additionally the pressor effect of sodium bicarbonate is much lower than that of equivalent amounts of sodium chloride. The aim of our work was to evaluate the effect of ingesting a sodium-rich carbonated mineral water (Agua das Pedras) on blood pressure values in normotensive individuals.

Methods: This crossover, non-blinded study evaluated 17 individuals (9 female and 8 male), aged 24-53 years, median body mass index (BMI) < 23, randomly allocated in two groups, ingesting 500 ml/day of Agua das Pedras or Agua Vitalis. Each arm of the study lasted 7 weeks, with 6 weeks of washout between them. Twenty-four hour urinary samples were collected at the beginning and end of each arm to determine pH and sodium and potassium excretion. Blood pressure and body weight were measured weekly throughout the study. A mixed-effects model was used to compare groups (p < 0.05). The Wilcoxon test was used to analyze electrolyte excretion.

Results: No differences were observed in blood pressure values between treatments or from baseline values. We found a positive correlation between BMI and blood pressure.

Discussion And Conclusions: The daily ingestion of 500 ml of Agua das Pedras had no effect on blood pressure. A study by Schorr and co-workers found that the ingestion of bicarbonate-rich water (1.5 l/day) had hypotensive effects in an elderly population. However, these results should be verified in hypertensive subjects, who are more likely to be salt sensitive, since in some of these individuals blood pressure rises even when sodium is ingested as sodium bicarbonate.
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February 2010

Modulation of adipocyte biology by δ(9)-tetrahydrocannabinol.

Obesity (Silver Spring) 2010 Nov 13;18(11):2077-85. Epub 2010 May 13.

Department of Biochemistry U38-FCT, Faculty of Medicine, University of Porto, Porto, Portugal.

It is recognized that the endocannabinoid system (ECS) plays a crucial role in the modulation of food intake and other aspects of energy metabolism. In this study, we aimed to investigate the effects of Δ(9)-tetrahydrocannabinol (THC) on adipocyte biology. 3T3-L1 cells were used to evaluate proliferation by sulforhodamine B (SRB) staining and methyl-(3)H-thymidine incorporation after 48 or 72 h of treatment with THC (1-500 nmol/l). Cells were differentiated in the presence or absence of the cannabinoid, and adipogenesis was determined by measuring lipid accumulation and peroxisome proliferator-activated receptor γ (PPARγ) transcription through reverse transcriptase-PCR (RT-PCR). Lipolysis was quantified under basal conditions or after isoproterenol (IP, 100 nmol/l) or insulin (INS, 100 nmol/l) treatment. Transforming growth factor β (TGFβ), diacylglycerol lipase α, and N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) transcriptions were determined by RT-PCR in preadipocytes and adipocytes and adiponectin only in adipocytes. THC treatment increased culture protein content and reduced methyl-(3)H-thymidine incorporation. Cells treated with THC underwent adipogenesis shown by the expression of PPARγ and had increased lipid accumulation. Basal and IP-stimulated lipolyses were inhibited by THC and there was no effect on lipolysis of INS-treated adipocytes. The effects on methyl-(3)H-thymidine incorporation and lipolysis seem to be mediated through CB1- and CB2-dependent pathways. THC decreased NAPE-PLD in preadipocytes and increased adiponectin and TGFβ transcription in adipocytes. These results show that the ECS interferes with adipocyte biology and may contribute to adipose tissue (AT) remodeling. Although these observations point toward increased AT deposition, the stimulation of adiponectin production and inhibition of lipolysis may be in favor of improved INS sensitivity under cannabinoid influence.
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http://dx.doi.org/10.1038/oby.2010.100DOI Listing
November 2010

Influence of river discharge patterns on the hydrodynamics and potential contaminant dispersion in the Douro estuary (Portugal).

Water Res 2010 May 31;44(10):3133-46. Epub 2010 Mar 31.

Laboratory of Hydrobiology, Institute of Biomedical Sciences (ICBAS), Universidade do Porto, Lg. Abel Salazar, 2, P-4099-003 Porto, Portugal.

Freshwater input to estuaries is a fundamental feature of these ecosystems, which may be profoundly altered by river damming as human needs for water consumption, irrigation or energy production increase. The Douro estuary is limited upstream by a dam since 1985, which reduced its length by ca. 60%. Freshwater inputs to the estuary are now irregular and greatly dependent on hydroelectric power demand; values ranging from zero to over 1000m(3)s(-1), in a matter of hours, especially in summer are common. In the present study, a three-dimensional hydrodynamic model was applied to the Douro estuary. The model was calibrated and validated against water elevation, current velocity, salinity and temperature data. Thereafter, it was used to analyse the effects of different flow regimes and magnitudes on estuarine hydrodynamics and contaminant dispersion. Results obtained suggest that the highly variable flow regimes, currently observed in the Douro, tend to reduce water column stratification and to enhance seawater intrusion, when compared with flow discharges of similar average magnitude, but lower variability. Stable flows seem to be the most effective in dispersing contaminants eventually introduced into the estuary through its small river tributaries. Overall results suggest that flow management may have important effects on estuarine hydrodynamics through non-linear interactions between flow magnitude and variability.
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http://dx.doi.org/10.1016/j.watres.2010.03.011DOI Listing
May 2010

The use of prealbumin concentration as a biomarker of nutritional status in treated phenylketonuric patients.

Ann Nutr Metab 2010 8;56(3):207-11. Epub 2010 Mar 8.

Centro de Genética Médica Jacinto de Magalhães, INSA, Porto, Portugal. julio.rocha @ insa.min-saude.pt

Background/aims: The neurological sequelae resulting from untreated phenylketonuria are diminished by the success of early introduced and continued dietary treatment. Nowadays, nutritional status is gaining importance in the follow-up of these patients. The aim of this work was to study the relevance of prealbumin concentration as biomarker of protein nutritional status of phenylketonuric patients.

Methods: We collected data from 69 phenylketonuric patients on food intake, blood prealbumin and blood phenylalanine concentrations. Protein insufficiency was defined as prealbumin z-scores below the 5th percentile of reference population. Additionally, we considered a prealbumin concentration of 20 mg/dl as a threshold level.

Results: Nine patients (13%) showed signs of protein insufficiency. When the threshold of 20 mg/dl for prealbumin was used, we found 38 patients (55%) with low prealbumin concentrations.

Conclusion: A significant group presented signs of protein insufficiency either using prealbumin z-scores or prealbumin concentration threshold, especially in milder forms of the disease. The results of this seem to confirm the already described threshold level for prealbumin concentration, suggesting that its measurement may be important for nutritional status evaluation, preventing protein insufficiency in milder forms of phenylketonuria.
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http://dx.doi.org/10.1159/000276641DOI Listing
July 2010

Absorption of anthocyanins through intestinal epithelial cells - Putative involvement of GLUT2.

Mol Nutr Food Res 2009 Nov;53(11):1430-7

Department of Chemistry, Chemistry Investigation Centre, University of Porto, Portugal.

Anthocyanins bioavailability is a major issue regarding their biological effects and remains unclear due to few data available on this matter. This work aimed to evaluate the absorption of anthocyanins at the intestine using Caco-2 cells. Anthocyanin extract, rich in malvidin-3-glucoside, was obtained from red grape skins and tested on Caco-2 cells. The absorption of anthocyanins, in absence or presence of 1% ethanol, was detected by HPLC/DAD/LC-MS. Our results showed that this transport was significantly increased in the presence of ethanol especially after 60 min of incubation. In addition, cells that were pretreated for 96 h with anthocyanins (200 microg/mL) showed an increase of their own transport (about 50% increase). Expression of glucose transporters sodium-dependent glucose transporter 1, facilitative glucose transporters 5, and facilitative glucose transporters 2 was assessed by RT-PCR. It was found that facilitative glucose transporters 2 expression was increased (60%) in Caco-2 cells pretreated with anthocyanins, by comparison with controls. When the effect of anthocyanin extract on (3)H-2-deoxy-D-glucose uptake was tested, an inhibitory effect was observed (about 60% decrease). However, the malvidin aglycone was tested and had no effect. In conclusion, anthocyanins could be absorbed through Caco-2 cells, and can interfere with their own transport and also with glucose intestinal uptake.
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http://dx.doi.org/10.1002/mnfr.200900007DOI Listing
November 2009

Comparison of the transport characteristics of bioactive substances in IUGR and normal placentas.

Pediatr Res 2009 Nov;66(5):495-500

Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, Porto, Portugal.

Knowing that IUGR is associated with altered placental transport, we aimed to characterize the placental transport of folic acid (FA), thiamine (THIAM), serotonin (5-HT), and 1-methyl-4-phenylpyridinium (MPP+) in IUGR. For this, we compared the transport characteristics of (3)H-FA, (3)H-THIAM, (3)H-5-HT, and (3)H-MPP+ in primary cultured human cytotrophoblasts isolated from IUGR and normal placentas (GRTB and NTB cells, respectively) and quantified mRNA expression of several placental transporters, by real-time RT-PCR. Our results show that GRTB cells take up (3)H-FA more efficiently (higher k(in) and A(max) values) and have higher transport capacity (higher V(max) values) for (3)H-FA, (3)H-5-HT, and (3)H-MPP+, when compared with NTB cells. In addition, GRTB cells take up (3)H-THIAM with higher affinity and (3)H-MPP+ with lower affinity than NTB cells. Finally, IUGR placentas have a generalized increase in mRNA expression of FA, THIAM, 5-HT, and MPP+ transporters, when compared with normal placentas, suggesting that the increase in transport capacity may be due to increased expression of placental transporters. These results point to an effect of "compensation for the weakness" of the IUGR placenta and pose the placenta as an active mediator of the communication between maternal and fetal environments.
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http://dx.doi.org/10.1203/PDR.0b013e3181b9b4a3DOI Listing
November 2009
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