The microsomal activation of aflatoxin B1 and 2-(N-ethylcarbamoyloxymethyl)furan in vitro using a novel diffusion apparatus

The activation by rat liver microsomal systems in vitro of a naturally occurring and a synthetic furan-containing toxin, aflatoxin B₁ and 2-(N-ethylcarbamoyloxymethyl)furan (CMF) has been examined. Both compounds are metabolised to form products which bind covalently to DNA and microsomal protein, Using a specially designed two-chamber diffusion apparatus it has been demonstrated that the active metabolite of CMF is able to bind covalently to DNA separated by a membrane barrier from the microsomal site of activation. In the case of aflatoxin B₁ the DNA must be in physical contact with the microsomal system for the active metabolite of aflatoxin B₁ to bind covalently. Differences between the activation of the two compounds have also been found with regard to their relative efficiencies in binding to DNA and also the effects of the nucleophile GSH. These results have suggested that if the molecular mechanisms of activation of the two compounds be similar, other factors, for example differences in lipid solubility, may play important roles in determining the relative biological activaties of the compounds. The results suggested that the subcellular site of activation of aflatoxin B₁, unlike that of CMF, may need to be adjacent to the target DNA. It is proposed that this site might be the outer nuclear membrane. Alternatively a carrier molecular might exist for the activated aflatoxin B₁ metabolite in vivo.     

The feasibility of an approximate irregular field dose distribution simulation program applied to a respiratory motion compensation system

PurposeThis study optimized our previously proposed simulation program for the approximate irregular field dose distribution (SPAD) and applied it to a respiratory motion compensation system (RMCS) and respiratory motion simulation system (RMSS). The main purpose was to rapidly analyze the two-dimensional dose distribution and evaluate the compensation effect of the RMCS during radiotherapy.MethodsThis study modified the SPAD to improve the rapid analysis of the dose distribution. In the experimental setup, four different respiratory signal patterns were input to the RMSS for actuation, and an ultrasound image tracking algorithm was used to capture the real-time respiratory displacement, which was input to the RMCS for actuation. A linear accelerator simultaneously irradiated the EBT3 film. The gamma passing rate was used to verify the dose similarity between the EBT3 film and the SPAD, and conformity index (CI) and compensation rate (CR) were used to quantify the compensation effect.ResultsThe Gamma passing rates were 70.48–81.39% (2%/2mm) and 88.23–96.23% (5%/3mm) for various collimator opening patterns. However, the passing rates of the SPAD and EBT3 film ranged from 61.85% to 99.85% at each treatment time point. Under the four different respiratory signal patterns, CR ranged between 21% and 75%. After compensation, the CI for 85%, 90%, and 95% isodose constraints were 0.78, 0.57, and 0.12, respectively.ConclusionsThis study has demonstrated that the dose change during each stage of the treatment process can be analyzed rapidly using the improved SPAD. After compensation, applying the RMCS can reduce the treatment errors caused by respiratory movements.     

Comparison of patient and staff temple dose during fluoroscopically guided coronary angiography,implantable cardiac devices,and electrophysiology procedures

There is a paucity of literature comparing patient and staff dose during coronary angiography (CA), implantable cardiac devices, permanent pacemakers (PPM) and electrophysiology (EP) procedures and little noting dose to staff other than cardiologists. This study sought to compare patient and occupational dose during a range of fluoroscopically guided cardiac procedures. Radiation dose levels for the patients (n = 1651), cardiologists (n = 24), scrub (n = 32) and scout nurses (n = 35) were measured in a prospective single-centre study between February 2017 and August 2019. A comparison of dose during CA, device implantation, PPM insertion and EP studies was performed. Three angiographic units were used, with dosimeters worn on the temple of staff. Results indicated that occupational dose during PPM was significantly higher than other procedures. The cardiologist had the highest mean dose during biventricular implantable cardioverter-defibrillators; levels were approximately five times that of ‘normal’ pacemaker insertions. Transcatheter aortic valve implantations (TAVI) were associated with relatively high mean doses for both staff and patients and had a statistically significant higher (>2 times) mean patient dose area product than all other categories. TAVI workups were also related to higher mean cardiologist and scrub nurse dose. It was observed that the mean scrub nurse dose can exceed that of the cardiologist. The highest mean dose for Scout nurses were recorded during EP studies. Given the significantly higher temple dose associated with PPM insertion, cardiologists should consider utilizing ceiling mounted lead shields, lead glasses and/or skull caps where possible. Efforts should also be made to minimize the use of DSA during TAVI and TAVI workups to reduce cardiologist, nurse and patient dose.     

Bisphenol A and Risk Management Ethics

It is widely recognized that endocrine disrupting compounds, such as Bisphenol A, pose challenges for traditional paradigms in toxicology, insofar as these substances appear to have a wider range of low‐dose effects than previously recognized. These compounds also pose challenges for ethics and policymaking. When a chemical does not have significant low‐dose effects, regulators can allow it to be introduced into commerce or the environment, provided that procedures and rules are in place to keep exposures below an acceptable level. This option allows society to maximize the benefits from the use of the chemical while minimizing risks to human health or the environment, and it represents a compromise between competing values. When it is not possible to establish acceptable exposure levels for chemicals that pose significant health or environmental risks, the most reasonable options for risk management may be to enact either partial or complete bans on their use. These options create greater moral conflict than other risk management strategies, leaving policymakers difficult choices between competing values.     

Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84?nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.     

Is volumetric modulated arc therapy with constant dose rate a valid option in radiation therapy for head and neck cancer patients?

Background

Intensity-modulated radiotherapy (IMRT) improves dose distribution in head and neck (HN) radiation therapy. Volumetric-modulated arc therapy (VMAT), a new form of IMRT, delivers radiation in single or multiple arcs, varying dose rates (VDR-VMAT) and gantry speeds, has gained considerable attention. Constant dose rate VMAT (CDR-VMAT) associated with a fixed gantry speed does not require a dedicated linear accelerator like VDR-VMAT. The present study explored the feasibility, efficiency and delivery accuracy of CDR-VMAT, by comparing it with IMRT and VDR-VMAT in treatment planning for HN cancer.

Absolute dose verification of static intensity modulated radiation therapy (IMRT) with ion chambers of various volumes and TLD detectors

Aim

This study aims at examining absolute dose verification of step-and-shoot intensity modulated radiation treatment (IMRT) of prostate and brain patients by use of ion chambers of two different volumes and thermoluminescent detectors (TLD).

Absorption ratio of treatment couch and effect on surface and build-up region doses

Aim

In this study, at different fields, energies and gantry angles, treatment couch and rails dose absorption ratio and treatment couch effect on surface and build-up region doses were examined.

Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors

Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.     

Homogeneous vs. patient specific breast models for Monte Carlo evaluation of mean glandular dose in mammography

PurposeTo compare, via Monte Carlo simulations, homogeneous and non-homogenous breast models adopted for mean glandular dose (MGD) estimates in mammography vs. patient specific digital breast phantoms.MethodsWe developed a GEANT4 Monte Carlo code simulating four homogenous cylindrical breast models featured as follows: (1) semi-cylindrical section enveloped in a 5-mm adipose layer; (2) semi-elliptical section with a 4-mm thick skin; (3) semi-cylindrical section with a 1.45-mm skin layer; (4) semi-cylindrical section in a 1.45-mm skin layer and 2-mm subcutaneous adipose layer. Twenty patient specific digital breast phantoms produced from a dedicated CT scanner were assumed as reference in the comparison. We simulated two spectra produced from two anode/filter combinations. An additional digital breast phantom was produced via BreastSimulator software.ResultsWith reference to the results for patient-specific breast phantoms and for W/Al spectra, models #1 and #3 showed higher MGD values by about 1% (ranges [–33%; +28%] and [−31%; +30%], respectively), while for model #4 it was 2% lower (range [−34%; +26%]) and for model #2 –11% (range [−39%; +14%]), on average. On the other hand, for W/Rh spectra, models #1 and #4 showed lower MGD values by 2% and 1%, while for model #2 and #3 it was 14% and 8% lower, respectively (ranges [−43%; +13%] and [−41%; +21%]). The simulation with the digital breast phantom produced with BreastSimulator showed a MGD overestimation of +33%.ConclusionsThe homogeneous breast models led to maximum MGD underestimation and overestimation of 43% and 28%, respectively, when compared to patient specific breast phantoms derived from clinical CT scans.