The bystander effect: Impact of rural hospital closures on the operations and financial well-being of surrounding healthcare institutions.

INTRODUCTION: There is presently a rural hospital shortage in the United States with 180 closures since 2005 and hundreds of institutions in financial peril. Although the hospital closure phenomenon is well-established, less is known about the spillover impact on the operations and financial wellbeing of surrounding hospitals. This preliminary study quantified how discrete rural hospital closures impact institutions in their regional proximity, finding a significant increase in inpatient admissions and emergency department visits for these "bystander hospitals". METHODS: Using a repository of rural hospital closures collected by the UNC Sheps Center for Health Services Research, we identified closures over the past 15 years. Criteria for inclusion were hospitals that had been fully closed between 2005-2016 and with >25-bed capacity. We then designated surrounding hospitals within a 30-mile radius of each closed hospital as "bystander hospitals." We examined the average rate-of-change for inpatient admissions and emergency department visits in surrounding hospitals both two years before and after relevant hospital closures. RESULTS: We identified 53 hospital closures and 93 bystander hospitals meeting our criteria during the study period. With respect to geographic distribution, 66% of closures were in the Southern US, including 21% in Appalachia. Average emergency department visits increased by 3.59% two years prior to a hospital's closure; however, at two years post-closure the average rate of increase rose to 10.22% (F (4,47) = 2.77, p = 0.0375). Average bystander hospital admissions fell by 5.73% in the two years preceding the hospital closure but increased 1.17% in the two years after (F (4,46) = 3.05, p = 0.0259). CONCLUSION: These findings predict a daunting future for rural healthcare. While previous literature has described the acute effects hospital closures have on communities, this study suggests a significant spillover effect on hospitals within the geographic region and a cyclical process at play in the rural healthcare sector. In the absence of significant public health assistance in regions affected by closures, poor health outcomes, including "diseases of despair," are likely to continue proliferating, disproportionately affecting the most vulnerable. In the COVID-19 era, it will be especially necessary to focus on hospital closures given increased risk of maintaining solvency due to delayed and deferred care atop already tight margins.

Effect of Optimized Versus Guidelines-Based Automated External Defibrillator Placement on Out-of-Hospital Cardiac Arrest Coverage: An In Silico Trial.

Background Mathematical optimization of automated external defibrillator (AED) placement may improve AED accessibility and out-of-hospital cardiac arrest (OHCA) outcomes compared with American Heart Association (AHA) and European Resuscitation Council (ERC) placement guidelines. We conducted an in silico trial (simulated prospective cohort study) comparing mathematically optimized placements with placements derived from current AHA and ERC guidelines, which recommend placement in locations where OHCAs are usually witnessed. Methods and Results We identified all public OHCAs of presumed cardiac cause from 2008 to 2016 in Copenhagen, Denmark. For the control, we computationally simulated placing 24/7-accessible AEDs at every unique, public, witnessed OHCA location at monthly intervals over the study period. The intervention consisted of an equal number of simulated AEDs placements, deployed monthly, at mathematically optimized locations, using a model that analyzed historical OHCAs before that month. For each approach, we calculated the number of OHCAs in the study period that occurred within a 100-m route distance based on Copenhagen's road network of an available AED after it was placed ("OHCA coverage"). Estimated impact on bystander defibrillation and 30-day survival was calculated by multivariate logistic regression. The control scenario involved 393 AEDs at historical, public, witnessed OHCA locations, covering 15.8% of the 653 public OHCAs from 2008 to 2016. The optimized locations provided significantly higher coverage (24.2%; P<0.001). Estimated bystander defibrillation and 30-day survival rates increased from 15.6% to 18.2% (P<0.05) and from 32.6% to 34.0% (P<0.05), respectively. As a baseline, the 1573 real AEDs in Copenhagen covered 14.4% of the OHCAs. Conclusions Mathematical optimization can significantly improve OHCA coverage and estimated clinical outcomes compared with a guidelines-based approach to AED placement.

Dose-Dependent Growth Delay of Breast Cancer Xenografts in the Bone Marrow of Mice Treated with 223Ra: The Role of Bystander Effects and Their Potential for Therapy.

The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with α-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Methods: Female Foxn1nu athymic nude mice were administered 0, 50, or 600 kBq/kg 223RaCl2 to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. Results: The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7- and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, α-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the α-particles emitted from 223Ra in bone for both MCF-7 and MDA-MB-231 cells. Conclusion: Taken together, these results support the participation of 223Ra-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using 223RaCl2 as an adjuvant treatment for select patients at early stages of breast cancer.

Exploring the Role of Race and Gender on Perceived Bystander Ability and Intent: Findings Before and After Exposure to an Online Training Program to Prevent Sexual Assault on Campus.

The current study explores the significance of race and gender on bystander attitudes before and after an online bystander intervention program to prevent sexual assault. A diverse sample of 750 college students participated in an online intervention and participants' perceived bystander intervention ability and intent were assessed. The interaction of participant race and gender had a marginally significant impact on bystander ability and intent baseline scores. Furthermore, when analyzing gain scores from pre- to posttest, there was a significant race by gender interaction. Specifically, Latinx and Black men had higher preintervention scores, and White men had higher gains postintervention. Relevant cultural and social factors and directions for future research are discussed.

Bystander Training as Leadership Training: Notes on the Origins, Philosophy, and Pedagogy of the Mentors in Violence Prevention Model.

This article outlines the origins, philosophy, and pedagogy of the Mentors in Violence Prevention (MVP) program, which has played a significant role in the gender violence prevention field since its inception in 1993. MVP was one of the first large-scale programs to target men for prevention efforts, as well as the first to operate systematically in sports culture and the U.S. military. MVP also introduced the "bystander" approach to the field. MVP employs a social justice, gender-focused approach to prevention. Key features of this approach are described and contrasted with individualistic, events-based strategies that have proliferated on college campuses and elsewhere in recent years.

Bar Training for Active Bystanders: Evaluation of a Community-Based Bystander Intervention Program.

Bystander intervention programs are proliferating on college campuses and are slowly gaining momentum as sexual violence prevention programs suitable for the larger community. In particular, bystander intervention programs aimed at bar staff have been developed in a number of locations. This study entails the exploratory evaluation of a community-based bystander program for bar staff. Using a pre-posttest design, this study suggests that evidence surrounding the effectiveness of this program is promising as it decreases rape myths, decreases barriers to intervention, and increases bartenders willingness to intervene. Future research and policy implications are discussed.

Comparative Assessment of Three Approaches of Teaching Nonmedically Trained Persons in the Handling of Supraglottic Airways: A Randomized Controlled Trial.

BACKGROUND: The use of supraglottic airways has been recommended in combat trauma airway management. To ensure an adequate airway management on the battlefield, suitable training concepts are sought to efficiently teach as many soldiers as possible. Our aim was to compare three approaches of teaching laypersons in the handling of supraglottic airways in a mannequin model. METHODS: In this prospective randomized blinded study, 285 military service men without any medical background were divided into three groups and trained in the use of the Laryngeal Mask Airway Supreme (LMA) and the Laryngeal Tube Disposable (LT-D). The first group received a theoretical lecture, the second group was shown an instruction video, and the third group underwent a practical training. Immediately after instruction participants were asked to place the supraglottic airway and ventilate the mannequin within 60 seconds. The entire test was repeated 3 months later. Test results were evaluated with regard to success rate, insertion time, ability to judge the correct placement, and degree of difficulty. RESULTS: Practical training showed the highest success rate when placing supraglottic airways immediately after the instruction (lecture: 68%, video: 74%, training: 94%); (training vs. lecture and training vs. video, p < 0.001) as well as 3 months later (lecture: 63%, video: 66%, training: 78%); (training vs. lecture, p = 0.019 and training vs. video, p = 0.025). Immediately after the instruction practical training was also superior in terms of insertion time, ability to judge the correct placement, and the self-rated degree of difficulty (p < 0.001). These effects were significantly reduced 3 months after the instruction. In comparison between supraglottic airways LT-D was superior to LMA regarding all the outcome parameters mentioned above (p < 0.001). DISCUSSION: In this study, performed with personnel of the German Armed Forces, we have shown that persons without any medical and paramedical background are able to successfully place a supraglottic airway immediately following minimal instruction and after 3 months as well. Study participants achieved the best results after practical training followed by video presentation and finally lecture regardless of the airway device used. There are two possible reasons why practical training is the superior method. Firstly, the success is tied to more time spent with the learners. Secondly, practical training seems to be the best teaching method for various types of learners such as visual, auditory, reading/writing, and kinesthetic type. In addition the results of our study show that the LT-D is an ideal supraglottic airway in the hands of people inexperienced in airway management. In conclusion, our results show that practical training is the superior instruction method compared to theoretical lecture and presentation of an instruction video. Nevertheless, the presentation of an instruction video is a promising approach of teaching a maximum number of laypersons with minimal effort to correctly place supraglottic airways. To optimize the success rate of such a concept LT-Ds instead of LMAs should be used for airway management. The presented concepts hold promise for combat as well as for civilian emergency medicine.

Mental Health First Aid in Rural Communities: Appropriateness and Outcomes.

PURPOSE: Mental Health First Aid (MHFA), an early intervention training program for general audiences, has been promoted as a means for improving population-level behavioral health (BH) in rural communities by encouraging treatment-seeking. This study examined MHFA's appropriateness and impacts in rural contexts. METHODS: We used a mixed-methods approach to study MHFA trainings conducted from November 2012 through September 2013 in rural communities across the country. DATA SOURCES: (a) posttraining questionnaires completed by 44,273 MHFA participants at 2,651 rural and urban trainings in 50 US states; (b) administrative data on these trainings; and (c) interviews with 16 key informants who had taught, sponsored, or participated in rural MHFA. Measure of Rurality: Rural-Urban Commuting Area Codes. ANALYSES: Chi-square tests were conducted on questionnaire data. Structural, descriptive, and pattern coding techniques were used to analyze interview data. FINDINGS: MHFA appears aligned with some key rural needs. MHFA may help to reduce unmet need for BH treatment in rural communities by raising awareness of BH issues and mitigating stigma, thereby promoting appropriate treatment-seeking. However, rural infrastructure deficits may limit some communities' ability to meet new demand generated by MHFA. MHFA may help motivate rural communities to develop initiatives for strengthening infrastructure, but additional tools and consultation may be needed. CONCLUSIONS: This study provides preliminary evidence that MHFA holds promise for improving rural BH. MHFA alone cannot compensate for weaknesses in rural BH infrastructure.

A biophysical model of cell evolution after cytotoxic treatments: Damage, repair and cell response.

We present a theoretical agent-based model of cell evolution under the action of cytotoxic treatments, such as radiotherapy or chemotherapy. The major features of cell cycle and proliferation, cell damage and repair, and chemical diffusion are included. Cell evolution is based on a discrete Markov chain, with cells stepping along a sequence of discrete internal states from 'normal' to 'inactive'. Probabilistic laws are introduced for each type of event a cell can undergo during its life: duplication, arrest, senescence, damage, reparation, or death. We adjust the model parameters on a series of cell irradiation experiments, carried out in a clinical LINAC, in which the damage and repair kinetics of single- and double-strand breaks are followed. Two showcase applications of the model are then presented. In the first one, we reconstruct the cell survival curves from a number of published low- and high-dose irradiation experiments. We reobtain a very good description of the data without assuming the well-known linear-quadratic model, but instead including a variable DSB repair probability. The repair capability of the model spontaneously saturates to an exponential decay at increasingly high doses. As a second test, we attempt to simulate the two extreme possibilities of the so-called 'bystander' effect in radiotherapy: the 'local' effect versus a 'global' effect, respectively activated by the short-range or long-range diffusion of some factor, presumably secreted by the irradiated cells. Even with an oversimplified simulation, we could demonstrate a sizeable difference in the proliferation rate of non-irradiated cells, the proliferation acceleration being much larger for the global than the local effect, for relatively small fractions of irradiated cells in the colony.

Assessment and Implications of Scattered Microbeam and Broadbeam Synchrotron Radiation for Bystander Effect Studies.

Synchrotron radiation is an excellent tool for investigating bystander effects in cell and animal models because of the well-defined and controllable configuration of the beam. Although synchrotron radiation has many advantages for such studies compared to conventional radiation, the contribution of dose exposure from scattered radiation nevertheless remains a source of concern. Therefore, the influence of scattered radiation on the detection of bystander effects induced by synchrotron radiation in biological in vitro models was evaluated. Radiochromic XRQA2 film-based dosimetry was employed to measure the absorbed dose of scattered radiation in cultured cells at various distances from a field exposed to microbeam radiotherapy and broadbeam X-ray radiation. The level of scattered radiation was dependent on the distance, dose in the target zone and beam mode. The number of γ-H2AX foci in cells positioned at the same target distances was measured and used as a biodosimeter to evaluate the absorbed dose. A correlation of absorbed dose values measured by the physical and biological methods was identified. The γ-H2AX assay successfully quantitated the scattered radiation in the range starting from 10 mGy and its contribution to the observed radiation-induced bystander effect.

Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach.

INTRODUCTION: In this study, we planned to assess if adult stem cell-based suicide gene therapy can efficiently eliminate glioblastoma cells in vivo. We investigated the therapeutic potential of mouse Oct4(-) bone marrow multipotent adult progenitor cells (mOct4(-) BM-MAPCs) in a mouse glioblastoma model, guided by multimodal in vivo imaging methods to identify therapeutic windows. METHODS: Magnetic resonance imaging (MRI) of animals, wherein 5 × 10(5) syngeneic enhanced green fluorescent protein-firefly luciferase-herpes simplex virus thymidine kinase (eGFP-fLuc-HSV-TK) expressing and superparamagnetic iron oxide nanoparticle labeled (1 % or 10 %) mOct4(-) BM-MAPCs were grafted in glioblastoma (GL261)-bearing animals, showed that labeled mOct4(-) BM-MAPCs were located in and in close proximity to the tumor. Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging). RESULTS: In the majority of GCV-treated, but not phosphate-buffered saline-treated animals, a significant difference was found in mOct4(-) BM-MAPC viability and tumor size at the end of treatment. Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells. CONCLUSIONS: Suicide gene therapy using mOct4(-) BM-MAPCs as cellular carriers was effective in reducing the tumor size in the majority of the GCV-treated animals leading to a longer progression-free survival compared to sham-operated animals. This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging. Noninvasive imaging is of particular interest for a rapid and efficient validation of stem cell-based therapeutic approaches for glioblastoma and hereby contributes to a better understanding and optimization of a promising therapeutic approach for glioblastoma patients.

Preclinical Efficacy and Safety Assessment of an Antibody-Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma.

PURPOSE: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody-drug conjugate (ADC) being developed for the treatment of breast cancer. EXPERIMENTAL DESIGN: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys. RESULTS: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy. CONCLUSIONS: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552-62. ©2015 AACR.

Use of synchrotron medical microbeam irradiation to investigate radiation-induced bystander and abscopal effects in vivo.

The question of whether bystander and abscopal effects are the same is unclear. Our experimental system enables us to address this question by allowing irradiated organisms to partner with unexposed individuals. Organs from both animals and appropriate sham and scatter dose controls are tested for expression of several endpoints such as calcium flux, role of 5HT, reporter assay cell death and proteomic profile. The results show that membrane related functions of calcium and 5HT are critical for true bystander effect expression. Our original inter-animal experiments used fish species whole body irradiated with low doses of X-rays, which prevented us from addressing the abscopal effect question. Data which are much more relevant in radiotherapy are now available for rats which received high dose local irradiation to the implanted right brain glioma. The data were generated using quasi-parallel microbeams at the biomedical beamline at the European Synchrotron Radiation Facility in Grenoble France. This means we can directly compare abscopal and "true" bystander effects in a rodent tumour model. Analysis of right brain hemisphere, left brain and urinary bladder in the directly irradiated animals and their unirradiated partners strongly suggests that bystander effects (in partner animals) are not the same as abscopal effects (in the irradiated animal). Furthermore, the presence of a tumour in the right brain alters the magnitude of both abscopal and bystander effects in the tissues from the directly irradiated animal and in the unirradiated partners which did not contain tumours, meaning the type of signal was different.

Radiation-induced bystander effect: early process and rapid assessment.

Radiation-induced bystander effect (RIBE) is a biological process that has received attention over the past two decades. RIBE refers to a plethora of biological effects in non-irradiated cells, including induction of genetic damages, gene expression, cell transformation, proliferation and cell death, which are initiated by receiving bystander signals released from irradiated cells. RIBE brings potential hazards to normal tissues in radiotherapy, and imparts a higher risk from low-dose radiation than we previously thought. Detection with proteins related to DNA damage and repair, cell cycle control, proliferation, etc. have enabled rapid assessment of RIBE in a number of research systems such as cultured cells, three-dimensional tissue models and animal models. Accumulated experimental data have suggested that RIBE may be initiated rapidly within a time frame as short as several minutes after radiation. These have led to the requirement of techniques capable of rapidly assessing RIBE itself as well as assessing the early processes involved.

Perspectives of brachytherapy: patterns of care, new technologies, and "new biology".

Brachytherapy has come a long way from its beginnings nearly a century ago. In recent years, brachytherapy has become ever more sophisticated thanks to a multitude of technological developments, including high-dose rate afterloading machines, image-guidance, and advanced planning systems. One of the advantages of brachytherapy, apart from the well-known capability of delivering highly conformal doses directly to the target, is that it is highly adaptable and can be used as a primary, adjunct, or salvage treatment. However, despite the existence of international treatment guidelines, the clinical practice of brachytherapy varies greatly by region, country, and even institution. In the present article, we provide an overview of recent findings from the Patterns of Care for Brachytherapy in Europe (PCBE) Study and we discuss new technologies used in brachytherapy and the emerging concept of "new biology" that supports the use of high-dose brachytherapy. Compared to the 1990s, the use of brachytherapy has increased substantially and it is expected to continue growing in the future as it becomes ever more precise and efficient.

Microdosimetric analysis confirms similar biological effectiveness of external exposure to gamma-rays and internal exposure to 137Cs, 134Cs, and 131I.

The risk of internal exposure to 137Cs, 134Cs, and 131I is of great public concern after the accident at the Fukushima-Daiichi nuclear power plant. The relative biological effectiveness (RBE, defined herein as effectiveness of internal exposure relative to the external exposure to γ-rays) is occasionally believed to be much greater than unity due to insufficient discussions on the difference of their microdosimetric profiles. We therefore performed a Monte Carlo particle transport simulation in ideally aligned cell systems to calculate the probability densities of absorbed doses in subcellular and intranuclear scales for internal exposures to electrons emitted from 137Cs, 134Cs, and 131I, as well as the external exposure to 662 keV photons. The RBE due to the inhomogeneous radioactive isotope (RI) distribution in subcellular structures and the high ionization density around the particle trajectories was then derived from the calculated microdosimetric probability density. The RBE for the bystander effect was also estimated from the probability density, considering its non-linear dose response. The RBE due to the high ionization density and that for the bystander effect were very close to 1, because the microdosimetric probability densities were nearly identical between the internal exposures and the external exposure from the 662 keV photons. On the other hand, the RBE due to the RI inhomogeneity largely depended on the intranuclear RI concentration and cell size, but their maximum possible RBE was only 1.04 even under conservative assumptions. Thus, it can be concluded from the microdosimetric viewpoint that the risk from internal exposures to 137Cs, 134Cs, and 131I should be nearly equivalent to that of external exposure to γ-rays at the same absorbed dose level, as suggested in the current recommendations of the International Commission on Radiological Protection.

Assessment of targeted and non-targeted responses in cells deficient in ATM function following exposure to low and high dose X-rays.

Radiation sensitivity at low and high dose exposure to X-rays was investigated by means of chromosomal aberration (CA) analysis in heterozygous ATM mutation carrier and A-T patient (biallelic ATM mutation) lymphoblastoid cell lines (LCLs). Targeted and non-targeted responses to acutely delivered irradiation were examined by applying a co-culture system that enables study of both directly irradiated cells and medium-mediated bystander effects in the same experimental setting. No indication of radiation hypersensitivity was observed at doses of 0.01 Gy or 0.1 Gy for the ATM mutation carrier LCL. The A-T patient cells also did not show low-dose response. There was significant increase in unstable CA yields for both ATM mutation carrier and A-T LCLs at 1 and 2 Gy, the A-T cells displaying more distinct dose dependency. Both chromosome and chromatid type aberrations were induced at an increased rate in the irradiated A-T cells, whereas for ATM carrier cells, only unstable chromosomal aberrations were increased above the level observed in the wild type cell line. No bystander effect could be demonstrated in any of the cell lines or doses applied. Characteristics typical for the A-T cell line were detected, i.e., high baseline frequency of CA that increased with dose. In addition, dose-dependent loss of cell viability was observed. In conclusion, CA analysis did not demonstrate low-dose (≤100 mGy) radiosensitivity in ATM mutation carrier cells or A-T patient cells. However, both cell lines showed increased radiosensitivity at high dose exposure.

Gap junction communication and the propagation of bystander effects induced by microbeam irradiation in human fibroblast cultures: the impact of radiation quality.

Understanding the mechanisms underlying the bystander effects of low doses/low fluences of low- or high-linear energy transfer (LET) radiation is relevant to radiotherapy and radiation protection. Here, we investigated the role of gap-junction intercellular communication (GJIC) in the propagation of stressful effects in confluent normal human fibroblast cultures wherein only 0.036-0.144% of cells in the population were traversed by primary radiation tracks. Confluent cells were exposed to graded doses from monochromatic 5.35 keV X ray (LET ~6 keV/µm), 18.3 MeV/u carbon ion (LET ~103 keV/µm), 13 MeV/u neon ion (LET ~380 keV/µm) or 11.5 MeV/u argon ion (LET ~1,260 keV/µm) microbeams in the presence or absence of 18-α-glycyrrhetinic acid (AGA), an inhibitor of GJIC. After 4 h incubation at 37°C, the cells were subcultured and assayed for micronucleus (MN) formation. Micronuclei were induced in a greater fraction of cells than expected based on the fraction of cells targeted by primary radiation, and the effect occurred in a dose-dependent manner with any of the radiation sources. Interestingly, MN formation for the heavy-ion microbeam irradiation in the absence of AGA was higher than in its presence at high mean absorbed doses. In contrast, there were no significant differences in cell cultures exposed to X-ray microbeam irradiation in presence or absence of AGA. This showed that the inhibition of GJIC depressed the enhancement of MN formation in bystander cells from cultures exposed to high-LET radiation but not low-LET radiation. Bystander cells recipient of growth medium harvested from 5.35 keV X-irradiated cultures experienced stress manifested in the form of excess micronucleus formation. Together, the results support the involvement of both junctional communication and secreted factor(s) in the propagation of radiation-induced stress to bystander cells. They highlight the important role of radiation quality and dose in the observed effects.

A simulation study of the radiation-induced bystander effect: modeling with stochastically defined signal reemission.

The radiation-induced bystander effect (RIBE) has been experimentally observed for different types of radiation, cell types, and cell culture conditions. However, the behavior of signal transmission between unirradiated and irradiated cells is not well known. In this study, we have developed a new model for RIBE based on the diffusion of soluble factors in cell cultures using a Monte Carlo technique. The model involves the signal emission probability from bystander cells following Poisson statistics. Simulations with this model show that the spatial configuration of the bystander cells agrees well with that of corresponding experiments, where the optimal emission probability is estimated through a large number of simulation runs. It was suggested that the most likely probability falls within 0.63-0.92 for mean number of the emission signals ranging from 1.0 to 2.5.

3D-modelling of radon-induced cellular radiobiological effects in bronchial airway bifurcations: direct versus bystander effects.

PURPOSE: The primary objective of this paper was to investigate the distribution of radiation doses and the related biological responses in cells of a central airway bifurcation of the human lung of a hypothetical worker of the New Mexico uranium mines during approximately 12 hours of exposure to short-lived radon progenies. MATERIALS AND METHODS: State-of-the-art computational modelling techniques were applied to simulate the relevant biophysical and biological processes in a central human airway bifurcation. RESULTS: The non-uniform deposition pattern of inhaled radon daughters caused a non-uniform distribution of energy deposition among cells, and of related cell inactivation and cell transformation probabilities. When damage propagation via bystander signalling was assessed, it produced more cell killing and cell transformation events than did direct effects. If bystander signalling was considered, variations of the average probabilities of cell killing and cell transformation were supra-linear over time. CONCLUSIONS: Our results are very sensitive to the radiobiological parameters, derived from in vitro experiments (e.g., range of bystander signalling), applied in this work and suggest that these parameters may not be directly applicable to realistic three-dimensional (3D) epithelium models.