Colorectal cancer is a major health problem worldwide with urgent need for new and effective anti... more Colorectal cancer is a major health problem worldwide with urgent need for new and effective anti-cancer approaches that allow treating, increasing survival and improving life quality of patients. At pharmacological concentrations, ascorbic acid (AA) exerts a selective cytotoxic effect, whose mechanism of cytotoxicity remains unsolved. It has been suggested that it depends on the production of extracellular hydrogen peroxide, using ascorbate radical as an intermediate. The aim of this study was to evaluate the effects induced by AA in three colon cancer cell lines, as well as, possible cell death mechanisms involved.
Our results showed that pharmacological concentrations of AA induce anti-proliferative, cytotoxic and genotoxic effects on three colon cancer cell lines under study. We also found that AA can induce cell death by an increment of oxidative stress, but also mediating a ROS-independent mechanism, as observed in LS1034 cells. This work explores AA anti-tumoral effects and highlights its applicability in the treatment of CC, underlying the importance of proceeding to clinical trials.
PURPOSE:
The purpose of this work was the development of an orthotopic model of osteosarcoma bas... more PURPOSE:
The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with (99m)Tc-sestamibi. METHODS:
Doxorubicin-sensitive (143B-luc(+)) and resistant (MNNG/HOS-luc(+)) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a (99m)Tc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of (99m)Tc-sestamibi washout half-life (t (1/2)), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio. RESULTS:
A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t (1/2) of (99m)Tc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc(+) tumours (t (1/2) = 87.3 +/- 15.7 min) than in drug-sensitive 143B-luc(+) tumours (t (1/2) = 161.0 +/- 47.4 min) and decreased significantly with PSC833 (t (1/2) = 173.0 +/- 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc(+) tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc(+) tumours than in 143B-luc(+) tumours at early (1.55 +/- 0.22 vs 2.14 +/- 0.36) and delayed times (1.12 +/- 0.11 vs 1.62 +/- 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour. CONCLUSION:
The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of (99m)Tc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.
Abstract The battle against cancer is so important that all possible weapons must be considered. ... more Abstract The battle against cancer is so important that all possible weapons must be considered. Photodynamic ther-apy (PDT) is a therapeutic approach which has proved its capacity to give many excellent results, but it is having some difficulty in being imposed. The ...
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor pro... more Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor prognosis and few therapeutic options. Radiotherapy is one of the most effective forms of cancer treatment, and P53 protein is one of the key molecules determining how a cell responds to radiotherapy. The aim of this study was to determine the therapeutic efficacy of iodine-131 in three human HCC cell lines. Western blotting was used to measure P53 expression. The effects of radiotherapy with iodine-131 were assessed by using the clonogenic assay to evaluate cell survival. Flow cytometry was carried out to examine the effects of iodine-131 on cell death, oxidative stress, reduced intracellular glutathione expression, the mitochondrial membrane potential, and the cell cycle. The P53 protein was not expressed in Hep3B2.1-7 cells, was expressed at normal levels in HepG2 cells, and was overexpressed in HuH7 cells. P53 expression in the HuH7 and HepG2 cell lines increased after internal and external irradiation with iodine-131. Irradiation induced a decrease in cell survival and led to a decrease in cell viability in all of the cell lines studied, accompanied by cell death via late apoptosis/necrosis and necrosis. Irradiation with 131-iodine induced mostly cell-cycle arrest in the G0/G1 phase. These results suggest that P53 plays a key role in the radiotherapy response of HCC.
Aim: Evaluate the microleakage of dental restorations using OptibondTM XTR (Kerr). The null hypot... more Aim: Evaluate the microleakage of dental restorations using OptibondTM XTR (Kerr). The null hypothesis was that the type adhesive system didn’t have influence in what concerns to microleakage. Materials and methods: Sixty noncarious extracted human molars were selected and cut in two equal halves occlusogingivally. Class V cavities (4/3/3 mm) were prepared on the buccal or lingual surfaces of each tooth with gingival margin walls in enamel. The specimens were divided randomly in four groups: (i) was applied OptibondTM XTR; (ii) was applied ClearfillTM SE BOND (Kuraray); (iii) the cavities weren’t restored; (iv) was applied OptibondTM XTR. In groups 1, 2 and 4 the enamel was conditioned (37% orthophosphoric acid) before the adhesive application and restored with SonicFillTM (Kerr). The specimens were stored in distilled water (37°C, 7 days) and after thermocycling (500 cycles, 5 and 55°C, dwell time 30’’). Two coats of nail polish were applied to the external surface around of each c...
1st Portuguese Meeting in Biomedical Engineering, ENBENG 2011, 2011
ABSTRACT In this work we describe a project that is currently in progress. We point out the key i... more ABSTRACT In this work we describe a project that is currently in progress. We point out the key ideas of the project explaining the pros and cons of the chosen approach. A clinic with image facilities produces a huge amount of information per year that, most of the times, is underused since exams are analyzed individually without the comparison between individuals or the exploration of features of a certain population. Data mining would be recommendable in these cases, however image databases are difficult to analyze because they depend on robust and automatic methods of segmentation and classification. We propose a method for segmenting nuclear medicine images (whole body PET scans) based on a classification method. The segmented regions are also labeled and used as additional features for a structured database.
ABSTRACT. The aim of the present study was to investigate the lymphatic cardiac circulation in an... more ABSTRACT. The aim of the present study was to investigate the lymphatic cardiac circulation in an experimental model of ischemia plus reperfusion in mongrel dogs (Canis familiaris L). As radiotracer we used 0.2-0.25 ml (111 MBq) of 99mTc-Re2S7 colloid (+/-10 microm), injected subcapsullary below the second diagonal of the descending anterior ligated coronary artery with a special needle. A gamma-camera/Starport + DecStation were used for data acquisition. Four experimental groups with five animals each were established: G I = controls; G II = immediately after acute myocardial infarction (AMI); G III = late infarction (5 days after AMI); G IV = ischemia (90 min) + reperfusion. Four regions of interest (ROIs) were chosen: injection area (ZA), above (ZB), near right (ZD), and far right (ZC) from ZA. Mean disappearance times in ZA and dynamic parameters in the other ROIs were determined from activity/time curves drawn in each area, using homemade software. The results obtained seem to indicate that the methodology is appropriate to a detailed study of lymphatic drainage in pathological situations in animal models.
More than 50% of liver tumours occur in patients aged 65 years or more. Assessment of functional ... more More than 50% of liver tumours occur in patients aged 65 years or more. Assessment of functional liver regeneration capacity is crucial to minimize postoperative liver failure. We aimed to study functional hepatocellular regeneration, through scintigraphic quantification of Mebrofenin hepatic extraction fraction (HEF), after partial hepatectomy, comparing elderly patients with younger ones. One hundred and two patients undergoing partial hepatectomy for primary or secondary hepatic lesions were prospectively included and divided in two groups: Group A - 58 patients aged &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;65 years (33 men, 53.9 ± 8.7 years), Group B - 44 patients aged ≥65 years (32 men, 71 ± 5 years). Groups were comparable in several aspects except for the presence of cirrhosis (more common in Group B, all patients Child-Pugh score A) and the initial diagnosis (Group B - primary lesions, Group A - metastases). The scintigraphic evaluation of Mebrofenin-HEF was performed before surgery, on the 5th and 30th day post-hepatectomy. Mortality and morbidity were 3.4 and 12.1%, respectively, in Group A and 2.3 and 11.4% in Group B (n.s.). HEF values (%), T1/2 (min) and Tmax (min) showed no significant differences between the two groups: Group A (preoperative: HEF = 99.2 ± 1.5%, T1/2 = 36.7 ± 21.3, Tmax = 15 ± 6. Day 5: HEF = 96.3 ± 10.8%, T1/2 = 76.4 ± 75.9; Tmax = 13.3 ± 4.9. Day 30: HEF = 98.4 ± 5.5%, T1/2 = 38.6 ± 7.7, Tmax = 12.8 ± 3.6) and Group B (preoperative: HEF = 95.3 ± 13%, T1/2 = 38.1 ± 24.1; Tmax = 15.9 ± 9.4. Day 5: HEF = 98.4 ± 2.6%, T1/2 = 106.6 ± 131.7; Tmax = 15.1 ± 6.2. Day 30: HEF = 99 ± 2.1%, T1/2 = 40.5 ± 27; Tmax = 15.5 ± 6.7). Our results suggest that functional hepatocellular regeneration is early, fast and similar between elderly and younger patients. Thus, age alone, does not appear to represent an absolute contraindication to hepatectomy.
Journal of the American College of Cardiology, 1995
ABSTRACT Collateral flow, even when developed after acute myocardial infarction (AMI), prevents t... more ABSTRACT Collateral flow, even when developed after acute myocardial infarction (AMI), prevents the progressive left ventricular dilation and remodeling after AMI. independent of infarct size reduction. The mechanisms underlying this situation are unknown. The purpose of this study was to examine the hypothesis that collateral flow influences the collagen volume fraction in the necrotic area. We studied ten mongrel dogs with AMI. The dogs were sacrificed five days later. The hearts were arrested in diastole, perfusion fixed, and sliced. Sections from each slice were taken from the center of the infarct zone, and stained with hematoxylin and eosin or picrosírius red. Collagen analysis was performed using polarized light microscopy. Using a random sampling morphometric technique, the relative density of collagen, was calculated. To confirm the results from morphometry fresh transmural myocardial tissue samples were also taken from the center of the infarct zone, and processed for measurement of hydroxiproline content (μg/mg dry tissue weight). Myocardial blood flow was measured with 99mTc labeled microspheres(10 μLm). Collagen deposition was analyzed in relation to baseline variables including the anatomic area at risk, necrosis, collateral blood flow and hemodynamic determinants of myocardial metabolic demand (heart rate, blood pressure, rate pressure product). Stepwise multivariate regression analysis showed that only collateral blood flow contributed to the model predicting an increase in myocardial collagen content (r2 = 0.89) P = 0.01. In conclusion, we found that after a myocardial infarction a rich collateral flow to the necrotic area is associated with an increase in the collagen content. This is probably one of the reasons why after AMI, collateral flow has a positive influence on ventricular remodeling, independent of infarct size reduction.
Journal of Labelled Compounds and Radiopharmaceuticals, 2014
(14)C-labeled saxagliptin, (13) CD2-labeled saxagliptin, and its (13) CD2-labeled 5-hydroxy metab... more (14)C-labeled saxagliptin, (13) CD2-labeled saxagliptin, and its (13) CD2-labeled 5-hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of (14)C-labeled saxagliptin was obtained with a specific activity of 53.98 μCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [(14)C]CH2 I2 starting material. By following similar synthetic routes, 580.0 mg of (13)CD2-labeled saxagliptin and 153.1 mg of (13)CD2-labeled 5-hydroxysaxagliptin metabolite were prepared.
Bone cancer can be divided into primary and secondary (metastatic) bone cancer. Osteosarcoma is t... more Bone cancer can be divided into primary and secondary (metastatic) bone cancer. Osteosarcoma is the most common type of primary bone cancer, but still is a rare cancer. The development of bone metastases is a common event for the cancer patient and the main cause of treatment failure and death, being chronic pain syndrome the most important complication. There are currently several therapeutic modalities for the treatment of metastatic bone disease, including radiation therapy. Treatment with radionuclides (β- and α-particle emitters and Auger electron cascades) is a safe and effective tool of medicine. There is a great deal of interest in diphosphonic acids in nuclear medicine as ligands for radiometals in bone-seeking diagnostic and therapeutic agents. Several radiopharmaceuticals have been designed with the phosphonates as ligands. A recent approach to develop an effective radiopharmaceutical for therapy of bone cancer was the design of a water-soluble polymer that would exploit the disrupted vasculature in tumors according to the enhanced permeability and retention effect. To enhance the effect of radionuclide therapy on the cancer cells, new strategies have recently been investigated, such as the combined radionuclide and chemotherapy, high-dose radionuclide therapy, and repeated radionuclide therapy.
Colorectal cancer is a major health problem worldwide with urgent need for new and effective anti... more Colorectal cancer is a major health problem worldwide with urgent need for new and effective anti-cancer approaches that allow treating, increasing survival and improving life quality of patients. At pharmacological concentrations, ascorbic acid (AA) exerts a selective cytotoxic effect, whose mechanism of cytotoxicity remains unsolved. It has been suggested that it depends on the production of extracellular hydrogen peroxide, using ascorbate radical as an intermediate. The aim of this study was to evaluate the effects induced by AA in three colon cancer cell lines, as well as, possible cell death mechanisms involved.
Our results showed that pharmacological concentrations of AA induce anti-proliferative, cytotoxic and genotoxic effects on three colon cancer cell lines under study. We also found that AA can induce cell death by an increment of oxidative stress, but also mediating a ROS-independent mechanism, as observed in LS1034 cells. This work explores AA anti-tumoral effects and highlights its applicability in the treatment of CC, underlying the importance of proceeding to clinical trials.
PURPOSE:
The purpose of this work was the development of an orthotopic model of osteosarcoma bas... more PURPOSE:
The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with (99m)Tc-sestamibi. METHODS:
Doxorubicin-sensitive (143B-luc(+)) and resistant (MNNG/HOS-luc(+)) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a (99m)Tc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of (99m)Tc-sestamibi washout half-life (t (1/2)), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio. RESULTS:
A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t (1/2) of (99m)Tc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc(+) tumours (t (1/2) = 87.3 +/- 15.7 min) than in drug-sensitive 143B-luc(+) tumours (t (1/2) = 161.0 +/- 47.4 min) and decreased significantly with PSC833 (t (1/2) = 173.0 +/- 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc(+) tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc(+) tumours than in 143B-luc(+) tumours at early (1.55 +/- 0.22 vs 2.14 +/- 0.36) and delayed times (1.12 +/- 0.11 vs 1.62 +/- 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour. CONCLUSION:
The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of (99m)Tc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.
Abstract The battle against cancer is so important that all possible weapons must be considered. ... more Abstract The battle against cancer is so important that all possible weapons must be considered. Photodynamic ther-apy (PDT) is a therapeutic approach which has proved its capacity to give many excellent results, but it is having some difficulty in being imposed. The ...
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor pro... more Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor prognosis and few therapeutic options. Radiotherapy is one of the most effective forms of cancer treatment, and P53 protein is one of the key molecules determining how a cell responds to radiotherapy. The aim of this study was to determine the therapeutic efficacy of iodine-131 in three human HCC cell lines. Western blotting was used to measure P53 expression. The effects of radiotherapy with iodine-131 were assessed by using the clonogenic assay to evaluate cell survival. Flow cytometry was carried out to examine the effects of iodine-131 on cell death, oxidative stress, reduced intracellular glutathione expression, the mitochondrial membrane potential, and the cell cycle. The P53 protein was not expressed in Hep3B2.1-7 cells, was expressed at normal levels in HepG2 cells, and was overexpressed in HuH7 cells. P53 expression in the HuH7 and HepG2 cell lines increased after internal and external irradiation with iodine-131. Irradiation induced a decrease in cell survival and led to a decrease in cell viability in all of the cell lines studied, accompanied by cell death via late apoptosis/necrosis and necrosis. Irradiation with 131-iodine induced mostly cell-cycle arrest in the G0/G1 phase. These results suggest that P53 plays a key role in the radiotherapy response of HCC.
Aim: Evaluate the microleakage of dental restorations using OptibondTM XTR (Kerr). The null hypot... more Aim: Evaluate the microleakage of dental restorations using OptibondTM XTR (Kerr). The null hypothesis was that the type adhesive system didn’t have influence in what concerns to microleakage. Materials and methods: Sixty noncarious extracted human molars were selected and cut in two equal halves occlusogingivally. Class V cavities (4/3/3 mm) were prepared on the buccal or lingual surfaces of each tooth with gingival margin walls in enamel. The specimens were divided randomly in four groups: (i) was applied OptibondTM XTR; (ii) was applied ClearfillTM SE BOND (Kuraray); (iii) the cavities weren’t restored; (iv) was applied OptibondTM XTR. In groups 1, 2 and 4 the enamel was conditioned (37% orthophosphoric acid) before the adhesive application and restored with SonicFillTM (Kerr). The specimens were stored in distilled water (37°C, 7 days) and after thermocycling (500 cycles, 5 and 55°C, dwell time 30’’). Two coats of nail polish were applied to the external surface around of each c...
1st Portuguese Meeting in Biomedical Engineering, ENBENG 2011, 2011
ABSTRACT In this work we describe a project that is currently in progress. We point out the key i... more ABSTRACT In this work we describe a project that is currently in progress. We point out the key ideas of the project explaining the pros and cons of the chosen approach. A clinic with image facilities produces a huge amount of information per year that, most of the times, is underused since exams are analyzed individually without the comparison between individuals or the exploration of features of a certain population. Data mining would be recommendable in these cases, however image databases are difficult to analyze because they depend on robust and automatic methods of segmentation and classification. We propose a method for segmenting nuclear medicine images (whole body PET scans) based on a classification method. The segmented regions are also labeled and used as additional features for a structured database.
ABSTRACT. The aim of the present study was to investigate the lymphatic cardiac circulation in an... more ABSTRACT. The aim of the present study was to investigate the lymphatic cardiac circulation in an experimental model of ischemia plus reperfusion in mongrel dogs (Canis familiaris L). As radiotracer we used 0.2-0.25 ml (111 MBq) of 99mTc-Re2S7 colloid (+/-10 microm), injected subcapsullary below the second diagonal of the descending anterior ligated coronary artery with a special needle. A gamma-camera/Starport + DecStation were used for data acquisition. Four experimental groups with five animals each were established: G I = controls; G II = immediately after acute myocardial infarction (AMI); G III = late infarction (5 days after AMI); G IV = ischemia (90 min) + reperfusion. Four regions of interest (ROIs) were chosen: injection area (ZA), above (ZB), near right (ZD), and far right (ZC) from ZA. Mean disappearance times in ZA and dynamic parameters in the other ROIs were determined from activity/time curves drawn in each area, using homemade software. The results obtained seem to indicate that the methodology is appropriate to a detailed study of lymphatic drainage in pathological situations in animal models.
More than 50% of liver tumours occur in patients aged 65 years or more. Assessment of functional ... more More than 50% of liver tumours occur in patients aged 65 years or more. Assessment of functional liver regeneration capacity is crucial to minimize postoperative liver failure. We aimed to study functional hepatocellular regeneration, through scintigraphic quantification of Mebrofenin hepatic extraction fraction (HEF), after partial hepatectomy, comparing elderly patients with younger ones. One hundred and two patients undergoing partial hepatectomy for primary or secondary hepatic lesions were prospectively included and divided in two groups: Group A - 58 patients aged &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;65 years (33 men, 53.9 ± 8.7 years), Group B - 44 patients aged ≥65 years (32 men, 71 ± 5 years). Groups were comparable in several aspects except for the presence of cirrhosis (more common in Group B, all patients Child-Pugh score A) and the initial diagnosis (Group B - primary lesions, Group A - metastases). The scintigraphic evaluation of Mebrofenin-HEF was performed before surgery, on the 5th and 30th day post-hepatectomy. Mortality and morbidity were 3.4 and 12.1%, respectively, in Group A and 2.3 and 11.4% in Group B (n.s.). HEF values (%), T1/2 (min) and Tmax (min) showed no significant differences between the two groups: Group A (preoperative: HEF = 99.2 ± 1.5%, T1/2 = 36.7 ± 21.3, Tmax = 15 ± 6. Day 5: HEF = 96.3 ± 10.8%, T1/2 = 76.4 ± 75.9; Tmax = 13.3 ± 4.9. Day 30: HEF = 98.4 ± 5.5%, T1/2 = 38.6 ± 7.7, Tmax = 12.8 ± 3.6) and Group B (preoperative: HEF = 95.3 ± 13%, T1/2 = 38.1 ± 24.1; Tmax = 15.9 ± 9.4. Day 5: HEF = 98.4 ± 2.6%, T1/2 = 106.6 ± 131.7; Tmax = 15.1 ± 6.2. Day 30: HEF = 99 ± 2.1%, T1/2 = 40.5 ± 27; Tmax = 15.5 ± 6.7). Our results suggest that functional hepatocellular regeneration is early, fast and similar between elderly and younger patients. Thus, age alone, does not appear to represent an absolute contraindication to hepatectomy.
Journal of the American College of Cardiology, 1995
ABSTRACT Collateral flow, even when developed after acute myocardial infarction (AMI), prevents t... more ABSTRACT Collateral flow, even when developed after acute myocardial infarction (AMI), prevents the progressive left ventricular dilation and remodeling after AMI. independent of infarct size reduction. The mechanisms underlying this situation are unknown. The purpose of this study was to examine the hypothesis that collateral flow influences the collagen volume fraction in the necrotic area. We studied ten mongrel dogs with AMI. The dogs were sacrificed five days later. The hearts were arrested in diastole, perfusion fixed, and sliced. Sections from each slice were taken from the center of the infarct zone, and stained with hematoxylin and eosin or picrosírius red. Collagen analysis was performed using polarized light microscopy. Using a random sampling morphometric technique, the relative density of collagen, was calculated. To confirm the results from morphometry fresh transmural myocardial tissue samples were also taken from the center of the infarct zone, and processed for measurement of hydroxiproline content (μg/mg dry tissue weight). Myocardial blood flow was measured with 99mTc labeled microspheres(10 μLm). Collagen deposition was analyzed in relation to baseline variables including the anatomic area at risk, necrosis, collateral blood flow and hemodynamic determinants of myocardial metabolic demand (heart rate, blood pressure, rate pressure product). Stepwise multivariate regression analysis showed that only collateral blood flow contributed to the model predicting an increase in myocardial collagen content (r2 = 0.89) P = 0.01. In conclusion, we found that after a myocardial infarction a rich collateral flow to the necrotic area is associated with an increase in the collagen content. This is probably one of the reasons why after AMI, collateral flow has a positive influence on ventricular remodeling, independent of infarct size reduction.
Journal of Labelled Compounds and Radiopharmaceuticals, 2014
(14)C-labeled saxagliptin, (13) CD2-labeled saxagliptin, and its (13) CD2-labeled 5-hydroxy metab... more (14)C-labeled saxagliptin, (13) CD2-labeled saxagliptin, and its (13) CD2-labeled 5-hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of (14)C-labeled saxagliptin was obtained with a specific activity of 53.98 μCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [(14)C]CH2 I2 starting material. By following similar synthetic routes, 580.0 mg of (13)CD2-labeled saxagliptin and 153.1 mg of (13)CD2-labeled 5-hydroxysaxagliptin metabolite were prepared.
Bone cancer can be divided into primary and secondary (metastatic) bone cancer. Osteosarcoma is t... more Bone cancer can be divided into primary and secondary (metastatic) bone cancer. Osteosarcoma is the most common type of primary bone cancer, but still is a rare cancer. The development of bone metastases is a common event for the cancer patient and the main cause of treatment failure and death, being chronic pain syndrome the most important complication. There are currently several therapeutic modalities for the treatment of metastatic bone disease, including radiation therapy. Treatment with radionuclides (β- and α-particle emitters and Auger electron cascades) is a safe and effective tool of medicine. There is a great deal of interest in diphosphonic acids in nuclear medicine as ligands for radiometals in bone-seeking diagnostic and therapeutic agents. Several radiopharmaceuticals have been designed with the phosphonates as ligands. A recent approach to develop an effective radiopharmaceutical for therapy of bone cancer was the design of a water-soluble polymer that would exploit the disrupted vasculature in tumors according to the enhanced permeability and retention effect. To enhance the effect of radionuclide therapy on the cancer cells, new strategies have recently been investigated, such as the combined radionuclide and chemotherapy, high-dose radionuclide therapy, and repeated radionuclide therapy.
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Papers by Maria Filomena Botelho
Our results showed that pharmacological concentrations of AA induce anti-proliferative, cytotoxic and genotoxic effects on three colon cancer cell lines under study. We also found that AA can induce cell death by an increment of oxidative stress, but also mediating a ROS-independent mechanism, as observed in LS1034 cells. This work explores AA anti-tumoral effects and highlights its applicability in the treatment of CC, underlying the importance of proceeding to clinical trials.
The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with (99m)Tc-sestamibi.
METHODS:
Doxorubicin-sensitive (143B-luc(+)) and resistant (MNNG/HOS-luc(+)) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a (99m)Tc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of (99m)Tc-sestamibi washout half-life (t (1/2)), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio.
RESULTS:
A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t (1/2) of (99m)Tc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc(+) tumours (t (1/2) = 87.3 +/- 15.7 min) than in drug-sensitive 143B-luc(+) tumours (t (1/2) = 161.0 +/- 47.4 min) and decreased significantly with PSC833 (t (1/2) = 173.0 +/- 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc(+) tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc(+) tumours than in 143B-luc(+) tumours at early (1.55 +/- 0.22 vs 2.14 +/- 0.36) and delayed times (1.12 +/- 0.11 vs 1.62 +/- 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour.
CONCLUSION:
The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of (99m)Tc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.
Our results showed that pharmacological concentrations of AA induce anti-proliferative, cytotoxic and genotoxic effects on three colon cancer cell lines under study. We also found that AA can induce cell death by an increment of oxidative stress, but also mediating a ROS-independent mechanism, as observed in LS1034 cells. This work explores AA anti-tumoral effects and highlights its applicability in the treatment of CC, underlying the importance of proceeding to clinical trials.
The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with (99m)Tc-sestamibi.
METHODS:
Doxorubicin-sensitive (143B-luc(+)) and resistant (MNNG/HOS-luc(+)) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a (99m)Tc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of (99m)Tc-sestamibi washout half-life (t (1/2)), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio.
RESULTS:
A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t (1/2) of (99m)Tc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc(+) tumours (t (1/2) = 87.3 +/- 15.7 min) than in drug-sensitive 143B-luc(+) tumours (t (1/2) = 161.0 +/- 47.4 min) and decreased significantly with PSC833 (t (1/2) = 173.0 +/- 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc(+) tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc(+) tumours than in 143B-luc(+) tumours at early (1.55 +/- 0.22 vs 2.14 +/- 0.36) and delayed times (1.12 +/- 0.11 vs 1.62 +/- 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour.
CONCLUSION:
The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of (99m)Tc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.