Lithium inelastic cross-sections and their impact on micro and nano dosimetry of boron neutron capture.

OBJECTIVE: To present a new set of lithium-ion cross-sections for (i) ionization and excitation processes down to 700 eV, and (ii) charge-exchange processes down to 1 keV/u. To evaluate the impact of the use of these cross-sections on micro a nano dosimetric quantities in the context of boron neutron capture (BNC) applications/techniques. Approach: The Classical Trajectory Monte Carlo (CTMC) method was used to calculate Li ion charge-exchange cross sections in the energy range of 1 keV/u to 10 MeV/u. Partial Li ion charge states ionization and excitation cross-sections were calculated using a detailed charge screening factor. The cross-sections were implemented in Geant4-DNA v10.07 and simulations and verified using TOPAS-nBio by calculating stopping power and CSDA range against data from ICRU and SRIM. Further microdosimetric and nanodosimetric calculations were performed to quantify differences against other simulation approaches for low energy Li ions. These calculations were: lineal energy spectra (yf(y) and yd(y)), frequency mean lineal energy (y_F ) ̅, dose mean lineal energy (y_D ) ̅ and ionization cluster size distribution analysis. Microdosimetric calculations were compared against a previous MC study that neglected charge-exchange and excitation processes. Nanodosimetric results were compared against pure ionization scaled cross-sections calculations. Main Results: Calculated stopping power differences between ICRU and Geant4-DNA decreased from 33.78% to 6.9%. The CSDA range difference decreased from 621% to 34% when compared against SRIM calculations. Geant4-DNA/TOPAS calculated dose mean lineal energy differed by 128% from the previous Monte Carlo. Ionization cluster size frequency distributions for Li ions differed by 76% to 344.11% for 21 keV and 2 MeV respectively. With a decrease in the N1 within 9% at 10 keV and agreeing after the 100 keV. With the new set of cross-sections being able to better simulate low energy behaviors of Li ions. Significance: This work shows an increase in detail gained from the use of a more complete set of low energy cross-sections which include charge exchange processes. Significant differences to previous simulation results were found at the microdosimetric and nanodosimetric scales that suggest that Li ions cause less ionizations per path length traveled but with more energy deposits. Microdosimetry results suggest that the BNC's contribution to cellular death may be mainly due to alpha particle production when boron-based drugs are distributed in the cellular membrane and beyond and by Li when it is at the cell cytoplasm regions.

Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA.

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.

Tumour microbiomes and Fusobacterium genomics in Vietnamese colorectal cancer patients.

Perturbations in the gut microbiome have been associated with colorectal cancer (CRC), with the colonic overabundance of Fusobacterium nucleatum shown as the most consistent marker. Despite its significance in the promotion of CRC, genomic studies of Fusobacterium is limited. We enrolled 43 Vietnamese CRC patients and 25 participants with non-cancerous colorectal polyps to study the colonic microbiomes and genomic diversity of Fusobacterium in this population, using a combination of 16S rRNA gene profiling, anaerobic microbiology, and whole genome analysis. Oral bacteria, including F. nucleatum and Leptotrichia, were significantly more abundant in the tumour microbiomes. We obtained 53 Fusobacterium genomes, representing 26 strains, from the saliva, tumour and non-tumour tissues of six CRC patients. Isolates from the gut belonged to diverse F. nucleatum subspecies (nucleatum, animalis, vincentii, polymorphum) and a potential new subspecies of Fusobacterium periodonticum. The Fusobacterium population within each individual was distinct and in some cases diverse, with minimal intra-clonal variation. Phylogenetic analyses showed that within four individuals, tumour-associated Fusobacterium were clonal to those isolated from non-tumour tissues. Genes encoding major virulence factors (Fap2 and RadD) showed evidence of horizontal gene transfer. Our work provides a framework to understand the genomic diversity of Fusobacterium within the CRC patients, which can be exploited for the development of CRC diagnostic and therapeutic options targeting this oncobacterium.

In vitro antifungal activity of Cinnamomum zeylanicum bark and leaf essential oils against Candida albicans and Candida auris.

Candida infections are a significant source of patient morbidity and mortality. Candida albicans is the most common pathogen causing Candida infections. Candida auris is a newly described pathogen that is associated with multi-drug-resistant candidiasis and candidaemia in humans. The antifungal effects of various essential oils and plant compounds have been demonstrated against human pathogenic fungi. In this study, the effect of cinnamon leaf and bark essential oils (CEOs) was determined against both C. albicans and C. auris. The disc diffusion (direct and vapour) and broth microdilution method was used to determine antifungal activity of the EOs against selected strains (C. albicans ATCC 10231, C. albicans ATCC 2091 and C. auris NCPF 8971) whilst the mode of action and haemolysin activity of the CEOs were determined using electron microscopy and light microscopy. Direct and vapour diffusion assays showed greater inhibitory activity of bark CEO in comparison with leaf CEO. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of bark CEO for all tested strains was below 0.03% (v/v), which was lower than the MICs of the leaf CEO (0.06-0.13%, v/v) dependent on the strain and the MFCs at 0.25% (v/v). In the morphological interference assays, damage to the cell membrane was observed and both CEOs inhibited hyphae formation. The haemolysin production assay showed that CEOs can reduce the haemolytic activity in the tested C. albicans and C. auris strains. At low concentrations, CEOs have potent antifungal and antihaemolytic activities in vitro against C. albicans and C. auris.Key points• Essential oils from Cinnamomum zeylanicum Blume bark and leaf (CBEO and CLEO) demonstrated fungicidal properties at very low concentrations.• The antifungal activity of CBEO was greater than that of CLEO consistent with other recent published literature.• The mode of action of CBEO and CLEO was damage to the membrane of C. albicans and C. auris.• Both CBEO and CLEO inhibited the formation of hyphae and reduced haemolysin production in C. albicans and C. auris. Graphical abstract.

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations.

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.

Electron track structure simulations in a gold nanoparticle using Geant4-DNA.

Gold Nanoparticles (GNPs) have recently gained a lot of attention due to their potential benefit to improve the efficacy of X-ray radiotherapy. Owing to their high atomic number, GNPs are able to absorb higher quantities of incident radiation with respect to the surrounding tissue, producing, in particular, photoelectrons and low energy Auger electrons. These additional low energy electrons increase the local energy deposition in the region surrounding the GNP. Monte Carlo simulations play a key role in the investigation of GNP radio-enhancement and it is widely recognised that track structure physics models are the state-of-the-art for nano-scale studies. In 2016, we have developed track structure physics models for the Geant4-DNA toolkit allowing electron transport for microscopic bulk gold (Geant4_DNA_AU_2016) and we have recently improved them in the low energy domain (Geant4_DNA_AU_2018). In this paper, we report the benchmarking of these newly developed physics models when calculating the physical dose and the Dose Enhancement Factor (DEF) around a GNP. We demonstrate that Geant4_DNA_AU_2018 models give similar azimuthal distribution of two dimensional absorbed dose around a single GNP, but result in larger absorbed dose and DEF than Geant4_DNA_AU_2016 models. In parallel, we investigated the performance of a newly developed multiple scattering model in Geant4 based on the Goudsmit-Saunderson (GS) model, when used together with the electromagnetic physics models with the Geant4 Livermore condensed-history approach. Our results show that the GS model does not affect the results of the simulations when studying GNP radio-enhancement with a condensed-history approach.

Evaluation of early radiation DNA damage in a fractal cell nucleus model using Geant4-DNA.

The advancement of multidisciplinary research fields dealing with ionising radiation induced biological damage - radiobiology, radiation physics, radiation protection and, in particular, medical physics - requires a clear mechanistic understanding of how cellular damage is induced by ionising radiation. Monte Carlo (MC) simulations provide a promising approach for the mechanistic simulation of radiation transport and radiation chemistry, towards the in silico simulation of early biological damage. We have recently developed a fully integrated MC simulation that calculates early single strand breaks (SSBs) and double strand breaks (DSBs) in a fractal chromatin based human cell nucleus model. The results of this simulation are almost equivalent to past MC simulations when considering direct/indirect strand break fraction, DSB yields and fragment distribution. The simulation results agree with experimental data on DSB yields within 13.6% on average and fragment distributions agree within an average of 34.8%.

Geant4-DNA track-structure simulations for gold nanoparticles: The importance of electron discrete models in nanometer volumes.

PURPOSE: Gold nanoparticles (GNPs) are known to enhance the absorbed dose in their vicinity following photon-based irradiation. To investigate the therapeutic effectiveness of GNPs, previous Monte Carlo simulation studies have explored GNP dose enhancement using mostly condensed-history models. However, in general, such models are suitable for macroscopic volumes and for electron energies above a few hundred electron volts. We have recently developed, for the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit, discrete physics models for electron transport in gold which include the description of the full atomic de-excitation cascade. These models allow event-by-event simulation of electron tracks in gold down to 10 eV. The present work describes how such specialized physics models impact simulation-based studies on GNP-radioenhancement in a context of x-ray radiotherapy. METHODS: The new discrete physics models are compared to the Geant4 Penelope and Livermore condensed-history models, which are being widely used for simulation-based NP radioenhancement studies. An ad hoc Geant4 simulation application has been developed to calculate the absorbed dose in liquid water around a GNP and its radioenhancement, caused by secondary particles emitted from the GNP itself, when irradiated with a monoenergetic electron beam. The effect of the new physics models is also quantified in the calculation of secondary particle spectra, when originating in the GNP and when exiting from it. RESULTS: The new physics models show similar backscattering coefficients with the existing Geant4 Livermore and Penelope models in large volumes for 100 keV incident electrons. However, in submicron sized volumes, only the discrete models describe the high backscattering that should still be present around GNPs at these length scales. Sizeable differences (mostly above a factor of 2) are also found in the radial distribution of absorbed dose and secondary particles between the new and the existing Geant4 models. The degree to which these differences are due to intrinsic limitations of the condensed-history models or to differences in the underling scattering cross sections requires further investigation. CONCLUSIONS: Improved physics models for gold are necessary to better model the impact of GNPs in radiotherapy via Monte Carlo simulations. We implemented discrete electron transport models for gold in Geant4 that is applicable down to 10 eV including the modeling of the full de-excitation cascade. It is demonstrated that the new model has a significant positive impact on particle transport simulations in gold volumes with submicron dimensions compared to the existing Livermore and Penelope condensed-history models of Geant4.

Magnetic resonance imaging appearance of the flexor carpi radialis tendon after harvest in ligamentous reconstruction tendon interposition arthroplasty.

OBJECTIVE: To determine whether the post-harvest magnetic resonance (MR) imaging appearance of flexor carpi radialis (FCR) tendons, harvested during ligamentous reconstruction tendon interposition (LRTI) of the thumb carpometacarpal (CMC) joint arthroplasty, is consistent with tendon regeneration. DESIGN: Operative reports and patient medical records for all patients undergoing LRTI arthroplasty between 1995 and 2003 at our institution were reviewed. MR images of the patients' forearms and wrists were obtained and interpreted by two musculoskeletal radiologists. Using the flexor carpi ulnaris (FCU) tendon as an internal standard, the extent of FCR tendon regeneration was expressed as a percentage by dividing the volume of regenerated FCR tendon by the volume of the FCU tendon. PATIENTS: Fourteen patients who had the full thickness of the FCR tendon harvested and who were available for MR imaging were identified and included in the study. RESULTS AND CONCLUSIONS: At least partial regeneration of the FCR tendon occurred in 11 of the 14 patients (79%). Of these, 2 patients (14%), demonstrated complete, or nearly complete regeneration. Partial regeneration of the FCR tendon was seen in 9 of the 14 patients (64%). In 3 patients (21%), there was no appreciable regeneration of the FCR tendon. Among patients who underwent full-thickness harvest of the FCR tendon for LRTI arthroplasty of the first CMC joint, the follow-up MR imaging appearance of the flexor carpi radialis tendon was consistent with tendon regeneration in 79% of those examined.

In vitro cyclic tensile testing of combined peripheral and core flexor tenorrhaphy suture techniques.

Early tenorrhaphy mobilization increases repair site strength and decreases adhesions. Preliminary unpublished data suggest that early active mobilization improves clinical outcome compared with traditional passive motion protocols. We loaded cadaver flexor profundus tendon repairs to 8.0 kg (78.4 N) for up to 5,000 cycles to simulate the loads and cycle number of our active flexor tendon rehabilitation protocol. 3-0 Ethibond (Ethicon, Somerville, NJ) and 6-0 Prolene (Surgi-pro; US Surgical, Norwalk, CT) were used for core and peripheral sutures, respectively. Four different groups were tested: 2-strand Tajima core suture with either a running interlocking (2R) or a Silfverskiöld cross-stitch (2S) peripheral suture and 4-strand Tajima plus horizontal mattress core suture with either a running interlocking (4R) or a Silfverskiöld peripheral suture (4S). Repairs failed in the suture midsubstance or at the knot. There was considerable variability within groups and no significant difference in the number of cycles to failure between the 2R, 4R, and 2S repairs, which failed after 2 +/- 2, 304 +/- 249, and 560 +/- 987 cycles, respectively. All 4S repairs were intact after 5,000 cycles. Our data suggest that flexor tenorrhaphy with the 4S repair can withstand the cyclic loads we estimate would be present during an active rehabilitation protocol.