Monte-Carlo simulation with FLUKA for liquid and solid targets

Introduction Monte-Carlo simulations can be used to assess isotope production on small medical cyclotrons. These simulations calculate the particle interactions with electric and magnetic fields, as well as the nuclear reactions. The results can be used to predict both yields and isotopic contaminations and can aid in the optimum design of target material and target geometry [1,2]. FLUKA is a general-purpose tool widely used in many applications from accelerator shielding to target design, calorimetry, activation, dosimetry, detector design, neutrino physics, or radiotherapy [3,4]. In this work, we applied the Monte-Carlo code FLUKA to determine the accuracy of predicting yields of various isotopes as compared to experimental yields. Material and Methods The proton beam collimation system, as well as the liquid and solid target of the TR13 cyclotron at TRIUMF, has been modeled in FLUKA. The proton beam parameters were initially taken from the cyclotron design specifications and were optimized against experimental measurements from the TR13. Data from irradiations of different targets and with different beam currents were collected in order to account for average behavior, see FIG. 1. Yields for a pencil proton beam as well as a beam spread out in direction and energy have been calculated and have been compared to experimental results obtained with the TR13. Results and Conclusion The reactions listed in TABLE 1 were assessed. For most reactions a good agreement was found in the comparison between experimental and simulated saturation yield. TABLE 1 only shows the yields simulated with a proton beam with a spread in both direction and energy. In most cases, the simulated yield is slightly larger or comparable. Only the calculated yield for 55Co was significantly lower by a factor of 4.2. This is still a good agreement considering that FLUKA was originally a high-energy physics code. It may indicate that the FLUKA internal cross-section calculation for this isotope production needs some optimization. In summary, we conclude that FLUKA can be used as a tool for the prediction of isotope production as well as for target design

Production of radiometals in a liquid target

Introduction Access to radiometals suitable for labeling novel molecular imaging agents requires that they be routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for a radiometal of interest is necessary, both of which can be significant hurdles in availability of less common isotopes. Herein, we describe the production of 44Sc, 68Ga, 89Zr, 86Y and 94mTc in a solution target which allows for the production of various radiometallic isotopes, enabling rapid isotope-biomolecule pairing optimization for tracer development. Work on solution targets has also been performed by other groups [e.g. 1, 2]. Material and Methods Solutions containing a high concentration of natural-abundance zinc nitrate, yttrium nitrate, calcium nitrate [3], strontium nitrate or ammonium heptamolybdate [4] were irradiated on a 13 MeV cyclotron using a standard liquid target. Some of the solutions contained additional hydrogen peroxide or nitric acid to improve solubility and reduce pressure rise in the target during irradiation. Yields calculated using theoretical cross sections (EMPIRE [5]) were compared to the measured yields. In addition, we tested a thermo-syphon target design for the production of 44Sc. Chemical separation of the product from the target material was carried out on a remote apparatus modeled after that of Siikanen [6]. Results and Conclusion The proposed approach enabled the production of quantities sufficient for chemical or biological studies for all metals discussed. In the case of 68Ga, activity up to 480 ± 22 MBq was obtained from a one hour run with a beam current of 7 µA, potentially enabling larger scale clinical production. Considering all reactions, the ratio of theoretical saturation yields to experimental yields ranges from 0.8 for 94mTc to 4.4 for 44Sc. The thermo-syphon target exhibited an increase of current on the target by a factor of 2.5 and an increase in yield by a factor of five for the production of 44Sc. Separation methods were developed for all isotopes and separation efficiency ranges from 71 ± 1 % for 94mTc to 99 ± 4 % for 86Y. 44Sc, 68Ga, and 86Y were successfully used in labeling studies with a model 1,4,7,10-tetrazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate, while 89Zr coordination behavior was tested using desferrioxamine-alkyne (DFO-alkyne). In summary, we present a promising new method to produce a suite of radiometals in a liquid target. Future work will continue to expand the list of radiometals and to apply this approach to the development of various peptide, protein and antibody radiotracers

Do people living with HIV experience greater age advancement than their HIV-negative counterparts?

OBJECTIVES: Despite successful antiretroviral (ARV) therapy, people living with HIV (PLWH) may show signs of premature/accentuated aging. We compared established biomarkers of aging in PLWH, appropriately-chosen HIV-negative individuals, and blood donors, and explored factors associated with biological age advancement. DESIGN: Cross-sectional analysis of 134 PLWH on suppressive ARV therapy, 79 lifestyle-comparable HIV-negative controls aged ≥45 years from the Co-morBidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors (BD). METHODS: Biological age was estimated using a validated algorithm based on ten biomarkers. Associations between 'age advancement' (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitis B (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression. RESULTS: The average (95% CI) age advancement was greater in both HIV-positive [13.2 (11.6, 14.9) years] and HIV-negative [5.5 (3.8, 7.2) years] COBRA participants compared to BD [-7.0 (-4.1, -9.9) years, both p's < 0.001)], but also in HIV-positive compared to HIV-negative participants (p < 0.001). Chronic HBV, higher anti-CMV IgG titer and CD8 T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, age advancement was increased by 3.5 (0.1, 6.8) years among those with nadir CD4 < 200 cells/μL and by 0.1 (0.06, 0.2) years for each additional month of exposure to saquinavir. CONCLUSIONS: Both treated PLWH and lifestyle-comparable HIV-negative individuals show signs of age advancement compared to BD, to which persistent CMV, HBV co-infection and CD8 T-cell activation may have contributed. Age advancement remained greatest in PLWH and was related to prior immunodeficiency and cumulative saquinavir exposure

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1)

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone. Methods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRIor PET-derived target volumes, rate of long term survivors (> 1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation. Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning. Trial registration: The GLIAA trial is registered with ClinicalTrials.gov (NCT01252459, registration date 02.12.2010), German Clinical Trials Registry (DRKS00000634, registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012)

Análise da implantação do sistema de gestão dos resíduos sólidos recicláveis na Vila das Peças, Guaraqueçaba, Paraná, Brasil

Objectives: Despite successful antiretroviral therapy, people living with HIV (PLWH) may show signs of premature/accentuated aging. We compared established biomarkers of aging in PLWH, appropriately chosen HIV-negative individuals, and blood donors, and explored factors associated with biological age advancement. Design: Cross-sectional analysis of 134 PLWH on suppressive antiretroviral therapy, 79 lifestyle-comparable HIV-negative controls aged 45 years or older from the Co-morBidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors. Methods: Biological age was estimated using a validated algorithm based on 10 biomarkers. Associations between ` age advancement' (biological minus chronological age) and HIV status/ parameters, lifestyle, cytomegalovirus (CMV), hepatitis B (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression. Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2 (11.6-14.9) years] and HIV-negative [5.5 (3.8-7.2) years] COBRA participants compared with blood donors [-7.0 (-4.1 to -9.9) years, both P's< 0.001)], but also in HIV-positive compared with HIV-negative participants (P< 0.001). Chronic HBV, higher anti-CMV IgG titer and CD8 thorn T-cell count were each associated with increased age advancement, independently of HIV-status/ group. Among HIV-positive participants, age advancement was increased by 3.5 (0.1-6.8) years among those with nadir CD4 thorn T-cell count less than 200 cells/ ml and by 0.1 (0.06-0.2) years for each additional month of exposure to saquinavir. Conclusion: Both treated PLWH and lifestyle-comparable HIV-negative individuals show signs of age advancement compared with blood donors, to which persistent CMV, HBV co-infection and CD8(+) T-cell activation may have contributed. Age advancement remained greatest in PLWH and was related to prior immunodeficiency and cumulative saquinavir exposure

Non-Metabolic Membrane Tubulation and Permeability Induced by Bioactive Peptides

BACKGROUND: Basic cell-penetrating peptides are potential vectors for therapeutic molecules and display antimicrobial activity. The peptide-membrane contact is the first step of the sequential processes leading to peptide internalization and cell activity. However, the molecular mechanisms involved in peptide-membrane interaction are not well understood and are frequently controversial. Herein, we compared the membrane activities of six basic peptides with different size, charge density and amphipaticity: Two cell-penetrating peptides (penetratin and R9), three amphipathic peptides and the neuromodulator substance P. METHODOLOGY/PRINCIPAL FINDINGS: Experiments of X ray diffraction, video-microscopy of giant vesicles, fluorescence spectroscopy, turbidimetry and calcein leakage from large vesicles are reported. Permeability and toxicity experiments were performed on cultured cells. The peptides showed differences in bilayer thickness perturbations, vesicles aggregation and local bending properties which form lipidic tubular structures. These structures invade the vesicle lumen in the absence of exogenous energy. CONCLUSIONS/SIGNIFICANCE: We showed that the degree of membrane permeabilization with amphipathic peptides is dependent on both peptide size and hydrophobic nature of the residues. We propose a model for peptide-induced membrane perturbations that explains the differences in peptide membrane activities and suggests the existence of a facilitated “physical endocytosis,” which represents a new pathway for peptide cellular internalization

Cognitive function and drivers of cognitive impairment in a European and a Korean cohort of people living with HIV

Although cognitive impairments are still prevalent in the current antiretroviral therapy era, limited investigations have compared the prevalence of cognitive disorder in people living with HIV (PLWH) and its determinants in different regions and ethnicities. We compared cognitive performance across six domains using comparable batteries in 134 PLWH aged ≥45 years from the COBRA study (Netherlands, UK), and 194 PLWH aged ≥18 years from the NeuroAIDS Project (South Korea). Cognitive scores were standardized and averaged to obtain domain and global T-scores. Associations with global T-scores were evaluated using multivariable regression and the ability of individual tests to detect cognitive impairment (global T-score ≤45) was assessed using the area-under-the-receiver-operating-characteristic curve (AUROC). The median (interquartile range) age of participants was 56 (51, 62) years in COBRA (88% white ethnicity, 93% male) and 45 (37, 52) years in NeuroAIDS (100% Korean ethnicity, 94% male). The rate of cognitive impairment was 18.8% and 18.0%, respectively (p = 0.86). In COBRA, Black-African ethnicity was the factor most strongly associated with cognitive function (11.1 [7.7, 14.5] lower scores vs. white ethnicity, p < 0.01), whereas in NeuroAIDS, age (0.6 [0.1, 1.3] per 10-year, p<0.01) and education (0.7 [0.5, 0.9] per year, p<0.01) were significantly associated with cognitive function with anemia showing only a weak association (−1.2 [−2.6, 0.3], p=0.12). Cognitive domains most associated with cognitive impairment were attention (AUROC = 0.86) and executive function (AUROC = 0.87) in COBRA and processing speed (AUROC = 0.80), motor function (AUROC = 0.78) and language (AUROC = 0.78) in NeuroAIDS. Two cohorts of PLWH from different geographical regions report similar rates of cognitive impairment but different risk factors and cognitive profiles of impairment

CNS Delivery Via Adsorptive Transcytosis

Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity—like the cationization strategy—as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics

Do people living with HIV experience greater age advancement than their HIV-negative counterparts?

Objectives: Despite successful antiretroviral therapy, people living with HIV (PLWH) may show signs of premature/accentuated aging. We compared established biomarkers of aging in PLWH, appropriately chosen HIV-negative individuals, and blood donors, and explored factors associated with biological age advancement. Design: Cross-sectional analysis of 134 PLWH on suppressive antiretroviral therapy, 79 lifestyle-comparable HIV-negative controls aged 45 years or older from the Co-mor- Bidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors. Methods: Biological age was estimated using a validated algorithm based on 10 biomarkers. Associations between ‘age advancement’ (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitis B (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression. Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2 (11.6–14.9) years] and HIV-negative [5.5 (3.8–7.2) years] COBRA participants compared with blood donors [7.0 (4.1 to 9.9) years, both P’s<0.001)], but also in HIV-positive compared with HIV-negative participants (P<0.001). Chronic HBV, higher anti-CMV IgG titer and CD8þ T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, age advancement was increased by 3.5 (0.1–6.8) years among those with nadir CD4þ T-cell count less than 200 cells/ml and by 0.1 (0.06–0.2) years for each additional month of exposure to saquinavir