Papers by Wilson Eduardo Malagon Roa
Radiotherapy and Oncology, 2006
Radiotherapy and Oncology, 2006
Clinical & Investigative Medicine, 2013
Purpose: Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cance... more Purpose: Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). Methods: Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. Re...
Clinical & Investigative Medicine, 2012
Purpose: MicroRNAs (miRNAs) post-transcriptionally regulate hundreds of gene targets involved in ... more Purpose: MicroRNAs (miRNAs) post-transcriptionally regulate hundreds of gene targets involved in tumorigenesis thereby controlling vital biological processes, including cellular proliferation, differentiation and apoptosis. MiRNA profiling is an emerging tool for the potential early detection of a variety of malignancies. This study was conducyed to assess the feasibility and methodological robustness of quantifying sputum miRNAs, employing quantitative real-time polymerase chain reaction (RT-qPCR) and cluster analysis on an optimized miRNA profile as a novel approach for the early detection of non-small cell lung cancer (NSCLC). Methods: The relative expressions of 11 miRNAs in sputum (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, and let-7a) in addition to U6 were retrospectively assessed in four NSCLC-positive and four negative controls. Subsequently, a set of five miRNAs (miR-21, miR-143, miR-155, miR-210, miR-372) was selected because...
Clinical & Investigative Medicine, 2008
Purpose: Nanotechnology is an emerging field with significant translational potential in medicine... more Purpose: Nanotechnology is an emerging field with significant translational potential in medicine. In this study, we applied gold nanoparticles (GNP) to enhance radiation sensitivity and growth inhibition in radiation-resistant human prostate cancer cells. Methods: Gold nanoparticles (GNPs) were synthesized using HAuCl4 as the gold particle source and NaBH4 as the reductant. Either thio-glucose or sodium citrate was then added to the solution separately to bind the GNPs to form thio-glucose-capped gold nanoparticles (Glu-GNP) and neutral gold nanoparticles (TGS-GNPs). Human prostate carcinoma DU-145 cells were exposed to vehicle, irradiation, 15nM TGS-GNPs, or 15nM Glu-GNPs, or GNPs plus irradiation. The uptake assays of GNP were performed using hemocytometer to count cells and the mass spectrometry was applied to calculate gold mass. The cytotoxicity induced by GNPs, irradiation, or GNPs plus irradiation was measured using a standard colorimetric MTT assay. Results: Exposure to Glu...
Clinical & Investigative Medicine, 2010
Purpose: Small non-coding microRNAs (miRNAs) are key components of cancer development and are con... more Purpose: Small non-coding microRNAs (miRNAs) are key components of cancer development and are considered as potential biomarkers for cancer diagnosis and treatment monitoring. This study investigated miRNA expression profiles of human cancer cells in order to develop a screening method for lung cancer. Methods: A series of lung cancer related miRNAs (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, let-7a) were selected as candidates for miRNA expression profiles of human lung cancer cell lines (A549, SK-mes-1). MicroRNA u6 was the endogenous control. Cancer cell lines for positive controls; breast MCF-7, prostate Du-145, and glioblastoma U118. The negative control was normal lung fibroblast cell line MRC-5. RT-PCR was performed on StepOnePlus (Applied Biosystem, USA). MiRNA expressions of malignant cells were compared with normal fibroblast cells as well as endogenous control (u6) using the thermal cycle at threshold. Assessment of miRNA exp...
International Journal of Radiation Oncology*Biology*Physics, 2017
To perform a subset analysis of survival outcomes in elderly patients with glioblastoma from a ra... more To perform a subset analysis of survival outcomes in elderly patients with glioblastoma from a randomized phase 3 trial comparing 2 short-course radiation therapy (RT) regimens in elderly and/or frail patients. The original trial population included elderly and/or frail patients with a diagnosis of glioblastoma. Patients joined the phase 3, randomized, multicenter, prospective, noninferiority trial; were assigned to 1 of 2 groups in a 1:1 ratio, either short-course RT (25 Gy in 5 fractions, arm 1) or commonly used RT (40 Gy in 15 fractions, arm 2); and were stratified by age (<65 years and ≥65 years), Karnofsky Performance Status (KPS), and extent of surgery. For the subset analysis in this study, only patients aged ≥65 years were evaluated (elderly and frail patients were defined as patients aged ≥65 years with KPS of 50%-70%; elderly and non-frail patients were defined as patients aged ≥65 years with KPS of 80%-100%); 61 of the 98 initial patients comprised the patient population, with 26 patients randomized to arm 1 and 35 to arm 2. In this unplanned analysis, the short-course RT results were not statistically significantly different from the results of commonly used RT in elderly patients. The median overall survival time was 6.8 months (95% confidence interval [CI], 4.5-9.1 months) in arm 1 and 6.2 months (95% CI, 4.7-7.7 months) in arm 2 (P=.936). The median progression-free survival time was 4.3 months (95% CI, 2.6-5.9 months) in arm 1 and 3.2 months (95% CI, 0.1-6.3 months) in arm 2 (P=.706). A short-course RT regimen of 25 Gy in 5 fractions is an acceptable treatment option for patients aged ≥65 years, mainly those with a poor performance status or contraindication to chemotherapy, which would be indicated in cases of methylated O6 methylguanine-DNA-methyltransferase promoter tumors.
Journal of Applied Clinical Medical Physics, 2007
Incorporation of positron emission tomography (PET) data into radiotherapy planning is currently ... more Incorporation of positron emission tomography (PET) data into radiotherapy planning is currently under investigation for numerous sites including lung, brain, head and neck, breast, and prostate. Accurate tumor-volume quantification is essential to the proper utilization of the unique information provided by PET. Unfortunately, target delineation within PET currently remains a largely unaddressed problem. We therefore examined the ability of three segmentation methods-thresholding, Sobel edge detection, and the watershed approach-to yield accurate delineation of PET target cross-sections. A phantom study employing well-defined cylindrical and spherical volumes and activity distributions provided an opportunity to assess the relative efficacy with which the three approaches could yield accurate target delineation in PET. Results revealed that threshold segmentation can accurately delineate target cross-sections, but that the Sobel and watershed techniques both consistently fail to correctly identify the size of experimental volumes. The usefulness of threshold-based segmentation is limited, however, by the dependence of the correct threshold (that which returns the correct area at each image slice) on target size.
Cureus, Jan 27, 2016
Cancer care in Alberta, Canada is publicly funded and provides patients with access to health car... more Cancer care in Alberta, Canada is publicly funded and provides patients with access to health care facilities and providers. The distribution of patients and health services across Alberta presents challenges to the delivery of cancer care, especially radiation therapy. In this study, we examined the association between patient and health system factors, the use of radiation therapy and survival outcomes in patients with stage III non-small cell lung cancer (NSCLC). The provincial cancer registry was used to identify all patients who presented with clinical stage III NSCLC, diagnosed from 2005 to 2007, in Alberta. Patient characteristics, diagnostic method, treatment modality and treatment outcomes were collected from provincial health information systems for analyses. Factors influencing overall survival (OS) were analyzed using Cox proportional hazards models. Nine hundred twenty-nine patients were identified. Sixty-two percent of patients received radiation therapy (RT) as part o...
IFAC Proceedings Volumes, 2010
We develop in this paper a new mathematical model of cancer cell growth under estrogen stimulatio... more We develop in this paper a new mathematical model of cancer cell growth under estrogen stimulation. Not only can this model be used to interpret the cell cycle process of cancer cells in the presence of estrogen, but it can also be used to predict long term evolution of cell population count (proliferation response) and to predict the concentrations of estrogen presented in a sample. This mathematical model is based on the "cell cycle phase-specific effect of estrogen" process. The parameters of this model are estimated using measured GH3 cell proliferation response provided by the Real-time Cell Electronic Sensor referred to as RT-CES. Experimental results show that the developed model is able to predict cell proliferation response to estrogen stimulation of different concentrations and to provide an estimation of estrogen concentrations using RT-CES data. Theses features of the proposed model might provide biological insights to oncologists and contribute to the treatment and prevention from some diseases related to estrogen stimulation such as breast cancer.
Molecular Pharmaceutics, 2016
Secondary macrophage cytotoxicity induced by nanoparticles was described before. The study aim wa... more Secondary macrophage cytotoxicity induced by nanoparticles was described before. The study aim was to investigate the role of secondary cytotoxic effect in a macrophage-lung cancer coculture model after nanoparticle treatment in the presence and absence of anti-inflammatory drugs. An in vitro coculture model composed of confluent alveolar macrophage MH-S and A-549 lung cancer cells separated by a 0.4 μm porous membrane was used in the study. Macrophages were treated with two sizes of gelatin nanoparticles and two sizes of poly(isobutyl cyanoacrylate) (PIBCA) nanoparticles, with and without doxorubicin as a chemotherapeutic drug. The treatment effect with and without the presence of antiinflammatory drug was studied using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide) assay. The model drugs were ibuprofen, celecoxib, prednisolone, dexamethasone, and methotrexate. Different nanoparticles in different sizes were synthesized with a range of physicochemical characteristics. Doxorubicin loaded nanoparticles were prepared with an entrapment efficiency of 82−83% for PIBCA and 39−42% for gelatin. Nanoparticle treatment of macrophages showed a secondary cytotoxic effect on A-549 cancer cells at 24 and 36 h, with a drop in cell viability of 40−62%. However, this effect was significantly reduced to 10−48% if the macrophages were exposed to anti-inflammatory drugs. When ibuprofen and celecoxib were used the cell viability rebounded between 24 and 36 h. For prednisolone, dexamethasone, and methotrexate the cell viability dropped further between 24 and 36 h. Macrophages exposed to nanoparticles show secondary cytotoxicity, which has a significant antitumor effect in the microclimate of the coculture model. The beneficial nanoparticle treatment effect was significantly reduced if nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, or methotrexate was given at the same time. The data suggest that antiinflammatory treatments can decrease the carrier-induced macrophage cytotoxicity and its antitumor effectiveness with chemotherapy.
Journal of neuro-oncology, Jul 15, 2016
We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integ... more We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1-3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deter...
Therapeutic delivery, 2016
Secondary toxicity of nanoparticles (NPs) in macrophages is a well-known phenomenon. The aim of t... more Secondary toxicity of nanoparticles (NPs) in macrophages is a well-known phenomenon. The aim of the study was to investigate the immuneresponse of macrophages after NP treatment. Antituberculosis drugs moxifloxacin and rifampicin were loaded into gelatin and polyisobutyl-cyanoacrylate NPs. The NPs were physicochemical characterized. Cellular immuneresponses and cellular viability were determined. The drug release kinetics vary depending on the type of NP, size and loading capacity. IC50 values of polyisobutyl-cyanoacrylate NPs were lower than for gelatin NPs. NPs treatment induced higher release of Th1 type cytokines compared with free drug. NPs together with chemotherapeutic drugs might be able to trigger an immune response in macrophages. The combined effect might be able to overcome mycobacteria infections.
Journal of Biological Chemistry, Feb 28, 2003
Fas, upon cross-linking with Fas ligand (FasL) or Fas agonistic antibody, transduces apoptotic ye... more Fas, upon cross-linking with Fas ligand (FasL) or Fas agonistic antibody, transduces apoptotic yet also proliferative signals, which have been implicated in tumor pathogenesis. In this study, we investigated the molecular mechanisms that control Fas-mediated signaling in glioma cells. Fas agonistic antibody, CH-11, induced apoptosis in sensitive glioma cells through caspase-8 recruitment to the Fas-mediated death-inducing signaling complex (DISC) where caspase-8 was cleaved to initiate apoptosis through a systematic cleavage of downstream substrates. In contrast, CH-11 stimulated cell growth in resistant glioma cells through recruitment of c-FLIP (cellular Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE)-inhibitory protein) to the Fas-mediated DISC. Three isoforms of long form c-FLIP were detected in glioma cells, but only the phosphorylated isoform was recruited to and cleaved into a p43 intermediate form in the Fas-mediated DISC in resistant cells. Calcium/calmodulindependent protein kinase II (CaMK II) activity was upregulated in resistant cells. Treatment of resistant cells with the CaMK II inhibitor KN-93 inhibited CaMK II activity, reduced c-FLIP expression, inhibited c-FLIP phosphorylation, and rescued CH-11 sensitivity. Transfection of CaMK II cDNA in sensitive cells rendered them resistant to CH-11. These results indicated that CaMK II regulates c-FLIP expression and phosphorylation, thus modulating Fas-mediated signaling in glioma cells. Fas (CD95 or APO-1) induces apoptosis upon stimulation with FasL 1 (CD95L or APO-1L) or an agonistic Fas antibody such as CH-11 (1-4). Fas is a type I transmembrane protein
Journal of Neuro-Oncology, 2015
Optimal treatment of recurrent glioblastoma multiforme (rGBM) in elderly and/or frail patients re... more Optimal treatment of recurrent glioblastoma multiforme (rGBM) in elderly and/or frail patients remains virtually unexplored, the best supportive care (BSC) only is routinely administered due to the fatal prognosis. We evaluated the impact of different treatment methods on post-progression survival (PPS) and overall survival (OS) of such patients. Data from 98 elderly and/or frail rGBM patients, treated initially with 1-week or 3-week radiotherapy (RT) within the phase III IAEA study (2010-2013), were analyzed. KPS at relapse and salvage treatment methods were recorded. Kaplan-Meier method was used to estimate PPS and OS for different treatment modalities. Eighty-four patients experienced recurrence: 47 (56 %) received BSC, 21 (25 %)-chemotherapy (CHT), 8 (9.5 %)-surgery, 3 (3.5 %)-RT, for 5 (6 %) the data was unavailable. Median OS from randomization for all 84 patients was 35 weeks: 55 versus 30 weeks for any treatment versus BSC, p < 0.0001. Median PPS was 15 weeks: 23 weeks with any treatment versus 9 weeks with BSC, p < 0.0001. For local treatment (surgery and/or RT) median PPS was 51 versus 21 weeks for CHT, p = 0.36. In patients with poor KPS (≤60) at relapse median PPS was 9 weeks with BSC versus 21 weeks with any treatment, p = 0.014. In poor KPS patients median PPS for local treatment was 14 weeks versus 21 weeks with CHT, p = 0.88. An active therapeutic approach may be beneficial for selected elderly and/or frail rGBM patients. Poor KPS patients may also benefit from active treatment, but there is no benefit of local treatment over CHT.
2004 International Conference on MEMS, NANO and Smart Systems (ICMENS'04)
This study aims to identify the intracellular locations of nanoparticles and liposomes carried by... more This study aims to identify the intracellular locations of nanoparticles and liposomes carried by aerosol "cluster bomb", and investigated the relative efficiencies of such drug delivery systems to kill cancer cells in vitro.
2004 International Conference on MEMS, NANO and Smart Systems (ICMENS'04)
ABSTRACT The aim of this study was to develop nanoparticles for lung delivery. Nanoparticles were... more ABSTRACT The aim of this study was to develop nanoparticles for lung delivery. Nanoparticles were incorporated into carrier particles using spray drying and a new spray-freeze drying technology. The carrier particles were manufactured with the appropriate size for pulmonary delivery. The new technology has important implications for local drug targeting and drug delivery of nanoparticle based delivery systems to the lungs.
2005 International Conference on MEMS,NANO and Smart Systems
ABSTRACT The aim of this study was to develop a new system of carrier particles and to optimize t... more ABSTRACT The aim of this study was to develop a new system of carrier particles and to optimize their Mass Median Aerodynamic Diameter (MMAD). We investigated different formulations and synthesized a new type of carrier particle, which releases nanoparticles actively. The active release mechanism of the nanoparticles from the carrier particles was achieved using sodium carbonate together with citric acid in a water solution. The MMAD of these formulations ranged from 2.8 to 3.60 μm. This study shows that it is possible to produce carrier particles loaded with nanoparticles with an appropriate MMAD to reach the deep area of the lungs.
International Journal of Pharmaceutics, 2004
Spray-drying is a common practice of powder preparation for a wide range of drugs. Spray-dried po... more Spray-drying is a common practice of powder preparation for a wide range of drugs. Spray-dried powders can be used to deliver particles to the lungs via a dry powder inhaler (DPI). The present study investigated the feasibility of developing a platform for aerosol delivery of nanoparticles. Lactose was used as the excipient and spray-dried with two different types of nanoparticles: gelatin and polybutylcyanoacrylate nanoparticles. Results showed that some carrier particles were hollow while others had a continuous matrix. Gelatin nanoparticles were incorporated throughout the matrix and sometimes accumulated at one end of the lactose. Polycyanoacrylate nanoparticles mostly clustered in different spots within the lactose carriers. The mean sizes of both nanoparticle types were characterized at two different times: before they were spray-dried and after they were redissolved from the spray-dried powders. Both nanoparticle types remained in the nano-range size after spray-drying. The mean nanoparticle sizes were increased by approximately 30% after spray-drying, though this increase was statistically significant only for the gelatin nanoparticles. Dispersion of the powder with an in-house passive dry powder inhaler and subsequent cascade impaction measurements showed that incorporation of the nanoparticles did not affect the fine particle fraction (FPF) or mass median aerodynamic diameter (MMAD) of the powders. FPF was approximately 40% while MMAD was 3.0 ± 0.2 m, indicating the present formulations yield aerosols of a suitable particle size for efficient lung delivery of nanoparticles. The present work demonstrates that nanoparticles can be delivered to the lungs via carrier particles that dissolve after coming in contact with the aqueous environment of the lung epithelium. This opens the way for new drug-targeting strategies using nanoparticles for pulmonary delivery of drugs and diagnostics.
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Papers by Wilson Eduardo Malagon Roa