The effect of metal based complexes on the survival of aerobic and hypoxic chinese hamster ovary cells, in vitro.

It is well established that many solid tumours are heterogeneous with respect to oxygenation, and contain regions of hypoxic cells, which due to their inherent resistance to ionizing radiation, limit the success of radiotherapy. Numerous chemicals and drugs have been investigated over the past few decades as potential radiosensitizers. The most notable of these being the organometallic compound, cis-diammine dichloroplatinum(II). The clinical success of this drug led to the synthesis of other types of organic cytotoxic metal-containing drugs. Prof. J.C. Swart from the University of the Orange Free State supplied seventeen novel iridium, ferrecenium and rhodium complexes, which I screened for cytotoxic activity against the CHO cell line. The two most cytotoxic complexes namely, [Rh(fctca)(cod)] and [Rh(fctfa)(cod)], were tested for radiosensitizing potential against aerobic and hypoxic CHO cells in the presence of an 8 MV photon beam by the MTT assay adapted to our laboratory conditions. The ferrocene betadiketones co-ordinated to them, Hfctca and Hfctfa and the Ir compliment of [Rh(fctfa)(cod)] namely, [Ir(fctfa)(cod)] were also assessed by the MTT assay. Interestingly, neither the ferrocene nor the iridium complexes showed noteworthy sensitization, which suggests that the rhodium is responsible for the efficacy observed. The radiosensitizing potential of the most active complex, [Rh(fctfa)(cod)] and cisplatin were also confirmed by the use of the more traditional clonogenic assay. Not only did the MTT assay deliver results comparable to the clonogenic technique, but one of the complexes [Rh(fctfa)(cod)] showed radiosensitizing potential against hypoxic CHO cells, equal to that of cisplatin. The rhodium complex, [Rh(fctfa)(cod)] was also tested for radiosensitization properties against the CHO cell line in the presence of a p(66)/Be neutron beam. Results indicated that [Rh(fctfa)(cod)] sensitizes cells to radiation possibly by inhibition of cell inactivation mechanisms that are normally associated with repairable damage. Consequent work done on the flow cytometer where direct DNA damage after irradiation (8 MV photon beam) and drug treatment, was assessed on aerobic CHO cells by a technique adapted to our laboratory showed no significant increase in the forward angle scattered light (FSC) parameter which is an indication of radiation induced strand breaks. Furthermore, [Rh(fctfa)(cod)] showed a significantly greater increase in the side angle scattered light (SSC) parameter, which is an indication of the binding ability of the complex, compared to cisplatin, after treatment with different concentrations of the drugs. Results obtained from enumerating micronuclei frequencies after drug treatment and radiation confirmed that both cisplatin and [Rh(fctfa)(cod)] are more active under hypoxic conditions, with [Rh(fctfa)(cod)] responsible for more micronuclei per binucleated cell. In conclusion, I have established that [Rh(fctfa)(cod)] has a cytotoxic activity comparable to that of cisplatin and that it sensitizes preferentially hypoxic CHO cells to radiation in the clinically relevant dose range. I have also identified the probable action by which [Rh(fctfa)(cod)] sensitizes CHO cells to radiation as being inhibition of repair capacity. Furthermore, results suggest that this complex binds covalently to DNA base pairs. The complex [Rh (fctfa) (cod)] , has so far proven to possess interesting radiosensitizing potential which must be exploited for eventual therapeutic benefit.Dissertation (MSc (Medical Physics))--University of Pretoria, 2007.Medical Oncologyunrestricte

Absorbed dose evaluation of Auger electron-emitting radionuclides: impact of input decay spectra on dose point kernels and S-values

The aim of this study was to investigate the impact of decay data provided by the newly developed stochastic atomic relaxation model BrIccEmis on dose point kernels (DPKs - radial dose distribution around a unit point source) and S-values (absorbed dose per unit cumulated activity) of 14 Auger electron (AE) emitting radionuclides, namely 67Ga, 80mBr, 89Zr, 90Nb, 99mTc, 111In, 117mSn, 119Sb, 123I, 124I, 125I, 135La, 195mPt and 201Tl. Radiation spectra were based on the nuclear decay data from the medical internal radiation dose (MIRD) RADTABS program and the BrIccEmis code, assuming both an isolated-atom and condensed-phase approach. DPKs were simulated with the PENELOPE Monte Carlo (MC) code using event-by-event electron and photon transport. S-values for concentric spherical cells of various sizes were derived from these DPKS using appropriate geometric reduction factors. The number of Auger and Coster-Kronig (CK) electrons and x-ray photons released per nuclear decay (yield) from MIRD-RADTABS were consistently higher than those calculated using BrIccEmis. DPKs for the electron spectra from BrIccEmis were considerably different from MIRD-RADTABS in the first few hundred nanometres from a point source where most of the Auger electrons are stopped. S-values were, however, not significantly impacted as the differences in DPKS in the sub-micrometre dimension were quickly diminished in larger dimensions. Overestimation in the total AE energy output by MIRD-RADTABS leads to higher predicted energy deposition by AE emitting radionuclides, especially in the immediate vicinity of the decaying radionuclides. This should be taken into account when MIRD-RADTABS data are used to simulate biological damage at nanoscale dimensions.Comment: 27 pages, 4 figures, 3 table

Carboxyhaemoglobin levels in water-pipe and cigarette smokers

Water-pipe smoking is growing in popularity, especially among young people, because of the social nature of the smoking session and the assumption that the effects are less harmful than those of cigarette smoking. It has however been shown that a single water-pipe smoking session produces a 24-hour urinary cotinine level equivalent to smoking 10 cigarettes per day. Aim. We aimed to measure carboxyhaemoglogin (COHb) blood levels before and after water-pipe and cigarette smoking sessions. Method. Self-confessed smokers older than 18 years (N=30) volunteered to smoke a water-pipe or a cigarette and have their blood COHb levels measured under controlled conditions. Results. Mean baseline COHb levels were 2.9% for the 15 cigarette smokers and 1.0% for the 15 water-pipe smokers. Levels increased by a mean of 481.7% in water-pipe smokers as opposed to 39.9% in cigarette smokers. Conclusion. The study demonstrated that water-pipe smokers had significantly higher increases in blood COHb levels than cigarette smokers during a single smoking session

Mobile phone radiation does not induce pro-apoptosis effects in human spermatozoa

Recent reports suggest that mobile phone radiation may diminish male fertility. However, the effects of this radiation on human spermatozoa are largely unknown. The present study examined effects of the radiation on induction of apoptosisrelated properties in human spermatozoa. Ejaculated, densitypurified, highly motile human spermatozoa were exposed to mobile phone radiation at specific absorption rates (SARs) of 2.0 and 5.7 W/kg. At various times after exposure, flow cytometry was used to examine caspase 3 activity, externalization of phosphatidylserine (PS), induction of DNA strand breaks, and generation of reactive oxygen species. Mobile phone radiation had no statistically significant effect on any of the parameters studied. This suggests that the impairment of fertility reported in some studies was not caused by the induction of apoptosis in spermatozoa.This research was funded by the National Research Foundation (NRF), Pretoria, South Africa (Grant No: 2054206), NRF mobility fund, the South African Bureau of Standards (SABS), Pretoria, South Africa and the Finnish Radiation and Nuclear Safety Authority (STUK), Helsinki, Finland

Mobile phone radiation does not induce pro-apoptosis effects in human spermatozoa

Recent reports suggest that mobile phone radiation may diminish male fertility. However, the effects of this radiation on human spermatozoa are largely unknown. The present study examined effects of the radiation on induction of apoptosisrelated properties in human spermatozoa. Ejaculated, densitypurified, highly motile human spermatozoa were exposed to mobile phone radiation at specific absorption rates (SARs) of 2.0 and 5.7 W/kg. At various times after exposure, flow cytometry was used to examine caspase 3 activity, externalization of phosphatidylserine (PS), induction of DNA strand breaks, and generation of reactive oxygen species. Mobile phone radiation had no statistically significant effect on any of the parameters studied. This suggests that the impairment of fertility reported in some studies was not caused by the induction of apoptosis in spermatozoa.This research was funded by the National Research Foundation (NRF), Pretoria, South Africa (Grant No: 2054206), NRF mobility fund, the South African Bureau of Standards (SABS), Pretoria, South Africa and the Finnish Radiation and Nuclear Safety Authority (STUK), Helsinki, Finland

The effect of pulsed 900-MHz GSM mobile phone radiation on the acrosome reaction, head morphometry and zona binding of human spermatozoa

Several recent studies have indicated that radiofrequency electromagnetic fields (RFEMF) have an adverse effect on human sperm quality, which could translate to an effect on fertilization potential. The present study evaluated the effect of RF-EMF on spermspecific characteristics in order to assess the fertilizing competence of sperm. Highly motile human spermatozoa, were exposed for one hour to 900 MHz mobile phone radiation at a specific absorption rate (SAR) of 2.0 W/kg and examined at various times after exposure. The acrosome reaction was evaluated using flow cytometry. The radiation did not affect sperm propensity for the acrosome reaction. Morphometric parameters were assessed by computer assisted sperm analysis (CASA). Significant reduction in sperm head area (9.2 ± 0.7 μm2 vs. 18.8 ± 1.4 μm2) and acrosome percentage of the head area (21.5 ± 4% vs. 35.5 ± 11.4%) were reported among exposed sperm compared with unexposed controls. Sperm–zona binding was assessed directly after exposure using the hemizona assay (HZA). The mean number of zona-bound sperm of the test hemizona and controls was 22.8 ± 12.4 and 31.8 ± 12.8 (p<0.05), respectively. This study concludes that while RF-EMF exposure did not adversely affect the acrosome reaction, it had a significant effect on sperm morphometry. In addition a significant decrease in sperm binding to the hemizona was observed. These results could indicate a significant effect of Several recent studies have indicated that radiofrequency electromagnetic fields (RFEMF) have an adverse effect on human sperm quality, which could translate to an effect on fertilization potential. The present study evaluated the effect of RF-EMF on spermspecific characteristics in order to assess the fertilizing competence of sperm. Highly motile human spermatozoa, were exposed for one hour to 900 MHz mobile phone radiation at a specific absorption rate (SAR) of 2.0 W/kg and examined at various times after exposure. The acrosome reaction was evaluated using flow cytometry. The radiation did not affect sperm propensity for the acrosome reaction. Morphometric parameters were assessed by computer assisted sperm analysis (CASA). Significant reduction in sperm head area (9.2 ± 0.7 μm2 vs. 18.8 ± 1.4 μm2) and acrosome percentage of the head area (21.5 ± 4% vs. 35.5 ± 11.4%) were reported among exposed sperm compared with unexposed controls. Sperm–zona binding was assessed directly after exposure using the hemizona assay (HZA). The mean number of zona-bound sperm of the test hemizona and controls was 22.8 ± 12.4 and 31.8 ± 12.8 (p<0.05), respectively. This study concludes that while RF-EMF exposure did not adversely affect the acrosome reaction, it had a significant effect on sperm morphometry. In addition a significant decrease in sperm binding to the hemizona was observed. These results could indicate a significant effect of RF-EMF on sperm fertilisation potential.This Research was funded by the National Research Foundation (NRF), Pretoria, South Africa (Grant No: 2054206), NRF mobility fund and the South African Bureau of Standards (SABS).http://www.blackwell-synergy.co

Absorbed dose evaluation of Auger electron-emitting radionuclides: impact of input decay spectra on dose point kernels and S-values

The aim of this study was to investigate the impact of decay data provided by the newly developed stochastic atomic relaxation model BrIccEmis on dose point kernels (DPKs - radial dose distribution around a unit point source) and S-values (absorbed dose per unit cumulated activity) of 14 Auger electron (AE) emitting radionuclides, namely 67Ga, 80mBr, 89Zr, 90Nb, 99mTc, 111In, 117mSn, 119Sb, 123I, 124I, 125I, 135La, 195mPt and 201Tl. Radiation spectra were based on the nuclear decay data from the medical internal radiation dose (MIRD) RADTABS program and the BrIccEmis code, assuming both an isolated-atom and condensed-phase approach. DPKs were simulated with the PENELOPE Monte Carlo (MC) code using event-byevent electron and photon transport. S-values for concentric spherical cells of various sizes were derived from these DPKs using appropriate geometric reduction factors. The number of Auger and Coster–Kronig (CK) electrons and x-ray photons released per nuclear decay (yield) from MIRD-RADTABS were consistently higher than those calculated using BrIccEmis. DPKs for the electron spectra from BrIccEmis were considerably different from MIRD-RADTABS in the first few hundred nanometres from a point source where most of the Auger electrons are stopped. S-values were, however, not significantly impacted as the differences in DPKs in the sub-micrometre dimension were quickly diminished in larger dimensions. Overestimation in the total AE energy output by MIRD-RADTABS leads to higher predicted energy deposition by AE emitting radionuclides, especially in the immediate vicinity of the decaying radionuclides. This should be taken into account when MIRD-RADTABS data are used to simulate biological damage at nanoscale dimensions.The authors gratefully acknowledge funding support from the Cancer Research-UK (C5255/ A15935), the Medical Research Council (MC_PC_12004), the Australian Research Council Discovery Grant (no. DP140103317) and the Generalitat de Catalunya (project no. 2014 SGR 846)

Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases

CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOBrain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of a-emitting radionuclides, Tb-149, At-211, Pb-212, Bi-213 and Ac-225|| beta-emitting radionuclides, Y-90, Tb-161 and Lu-177|| and Auger electron (AE)-emitters Ga-67, Zr-89, In-111 and I-124, for targeted radionuclide therapy (TRT). METHODS: Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative beta- and alpha-emitters, Lu-177 and Pb-212. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. RESULTS: Lu-177 produced 2.69 +/- 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 mu m. The DSB yield of Pb-212 included two local maxima produced by the 6.1 MeV and 8.8 MeV alpha-emissions from decay products, Bi-212 and Po-212, with yields of 7.64 +/- 0.12 and 9.15 +/- 0.24 per GbpGy, respectively. Given its higher DSB yield Pb-212 may be more effective for short range targeting of early micrometastatic lesions than Lu-177. CONCLUSION: MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of alpha-, beta- and AE-emitting radionuclides for TRT. Pb-212, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE.81292303CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO306775/2015-8190154/2013-6Agências de fomento estrangeiras apoiaram essa pesquisa, mais informações acesse artig

Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy

Molecular radiotherapy using 177Lu-DOTATATE is a most effective treatment for somatostatin receptor-expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after 177Lu-DOTATATE therapy using SPECT imaging with 111In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external-beam radiotherapy (EBRT) or 177Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor-positive tumor xenografts were treated with 17

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions