MR compatible detectors assessment for a 0.35 T MR-linac commissioning.

PURPOSE: To assess a large panel of MR compatible detectors on the full range of measurements required for a 0.35 T MR-linac commissioning by using a specific statistical method represented as a continuum of comparison with the Monte Carlo (MC) TPS calculations. This study also describes the commissioning tests and the secondary MC dose calculation validation. MATERIAL AND METHODS: Plans were created on the Viewray TPS to generate MC reference data. Absolute dose points, PDD, profiles and output factors were extracted and compared to measurements performed with ten different detectors: PTW 31010, 31021, 31022, Markus 34045 and Exradin A28 MR ionization chambers, SN Edge shielded diode, PTW 60019 microdiamond, PTW 60023 unshielded diode, EBT3 radiochromic films and LiF µcubes. Three commissioning steps consisted in comparison between calculated and measured dose: the beam model validation, the output calibration verification in four different phantoms and the commissioning tests recommended by the IAEA-TECDOC-1583. MAIN RESULTS: The symmetry for the high resolution detectors was higher than the TPS data of about 1%. The angular responses of the PTW 60023 and the SN Edge were - 6.6 and - 11.9% compared to the PTW 31010 at 60°. The X/Y-left and the Y-right penumbras measured by the high resolution detectors were in good agreement with the TPS values except for the PTW 60023 for large field sizes. For the 0.84 × 0.83 cm2 field size, the mean deviation to the TPS of the uncorrected OF was - 1.7 ± 1.6% against - 4.0 ± 0.6% for the corrected OF whereas we found - 4.8 ± 0.8% for passive dosimeters. The mean absolute dose deviations to the TPS in different phantoms were 0 ± 0.4%, - 1.2 ± 0.6% and 0.5 ± 1.1% for the PTW 31010, PTW 31021 and Exradin A28 MR respectively. CONCLUSIONS: The magnetic field effects on the measurements are considerably reduced at low magnetic field. The PTW 31010 ionization chamber can be used with confidence in different phantoms for commissioning and QA tests requiring absolute dose verifications. For relative measurements, the PTW 60019 presented the best agreement for the full range of field size. For the profile assessment, shielded diodes had a behaviour similar to the PTW 60019 and 60023 while the ionization chambers were the most suitable detectors for the symmetry. The output correction factors published by the IAEA TRS 483 seem to be applicable at low magnetic field pending the publication of new MR specific values.

microRNA blood signature for localized radiation injury.

A radiological accident, whether from industrial, medical, or malicious origin, may result in localized exposure to high doses of ionizing radiations, leading to the development of local radiation injury (LRI), that may evolve toward deep ulceration and necrosis of the skin and underlying tissues. Early diagnosis is therefore crucial to facilitate identification and management of LRI victims. Circulating microRNAs (miRNA) have been studied as potential diagnostic biomarkers of several diseases including hematological defects following whole-body irradiation (WBI). This study aims to identify a blood miRNA signature associated with LRI in a preclinical C57BL/6J mouse model of hindlimb irradiation using different 10-MV X-ray doses that lead to injuries of different severities. To this end, we first performed broad-spectrum plasma miRNA profiling, followed by a targeted validation step, on two independent animal cohorts. Using a multivariate sparse partial least square discriminant analysis, we identified a panel of eight circulating miRNAs able to segregate mice according to LRI severity. Interestingly, these miRNAs were previously associated with WBI (miR-150-5p, miR-342-3p, miR-146a-5p), inflammation (miR-18a-5p, miR-148b-3p, miR-532-5p) and skin diseases (miR-139-5p, miR-195-5p). Our results suggest the use of circulating miRNAs as suitable molecular biomarkers for LRI prognosis and diagnosis.

Inflammatory cells dynamics control neovascularization and tissue healing after localized radiation induced injury in mice.

Local overexposure to ionizing radiation leads to chronic inflammation, vascular damage and cachexia. Here we investigate the kinetics of inflammatory cells from day (D)1 to D180 after mouse hindlimb irradiation and analyze the role of monocyte (Mo) subsets in tissue revascularization. At D1, we find that Mo and T cells are mobilized from spleen and bone marrow to the blood. New vessel formation during early phase, as demonstrated by ~1.4- and 2-fold increased angiographic score and capillary density, respectively, correlates with an increase of circulating T cells, and Mohi and type 1-like macrophages in irradiated muscle. At D90 vascular rarefaction and cachexia are observed, associated with decreased numbers of circulating Molo and Type 2-like macrophages in irradiated tissue. Moreover, CCR2- and CX3CR1-deficency negatively influences neovascularization. However adoptive transfer of Mohi enhances vessel growth. Our data demonstrate the radiation-induced dynamic inflammatory waves and the major role of inflammatory cells in neovascularization.

Circulating microvesicles correlate with radiation proctitis complication after radiotherapy.

In a large retrospective study, we assessed the putative use of circulating microvesicles (MVs), as innovative biomarkers of radiation toxicity in a cohort of 208 patients with prostate adenocarcinoma overexposed to radiation. The level of platelet (P)-, monocyte (M)- and endothelial (E)-derived MVs were assessed by flow cytometry. Rectal bleeding toxicity scores were collected at the time of blood sampling and during the routine follow-up and were tested for association with MVs using a multivariate logistic regression. MVs dosimetric correlation was investigated using dose volume histograms information available for a subset of 36 patients. The number of PMVs was significantly increased in patients with highest toxicity grades compared to lower grades. Risk prediction analysis revealed that increased numbers of PMVs, and an increased amount of MMVs relative to EMVs, were associated with worst rectal bleeding grade compared to the time of blood sampling. Moreover, a significant correlation was found between PMV and MMV numbers, with the range of doses up to the median exposure (40 Gy) of bladder/rectum and anterior rectal wall, respectively. MVs could be considered as new biomarkers to improve the identification of patients with high toxicity grade and may be instrumental for the prognosis of radiation therapy complications.

Symptoms of Depression and Anxiety in Adults with High-Grade Glioma: A Literature Review and Findings in a Group of Patients before Chemoradiotherapy and One Year Later.

High-grade glioma (HGG) is associated with several external and internal stressors that may induce mood alterations at all stages of the disease. Symptoms of depression and anxiety in persons with glioma have multifactorial etiology and require active follow-up. We reviewed the literature data on the prevalence, mechanisms likely involved in the etiology of mood alterations in persons with HGG and psychosocial interventions found beneficial in treating these symptoms. We also investigated the prevalence and clinical variables that could increase the risk of depression and anxiety symptoms in a group of patients with HGG at two disease time-points: after surgery, before and 1 year after chemoradiotherapy. Literature findings revealed complex mechanisms underlying these symptoms and highlighted the importance of providing early access to palliative care. Our results show a high rate of anxiety and depression symptoms in the first stage of the disease and increased concomitance of these symptoms at the 1-year follow-up. Depression and anxiety symptoms at 1 year after the end of chemoradiotherapy were associated with the presence of symptoms at the first stage of the disease and tumor progression. Antiepileptic drugs and corticosteroid intake did not increase the risk of depressive and anxious symptoms among patients. Active management of mood alterations is an essential part of the care and contributes to patients' well-being and quality of life.

Molecular Changes In Cardiac Tissue As A New Marker To Predict Cardiac Dysfunction Induced By Radiotherapy.

The contribution of radiotherapy, per se, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and 27.6 Gy, respectively. We demonstrate that myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of >15% from baseline) in a dose-dependent manner at 18 months. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Before GLS impairment detection, several tools (qRT-PCR, mass spectrometry, and western blot) were used to assess molecular changes in the cardiac tissue. The number/expression of several genes, proteins, and KEGG pathways, related to inflammation, fibrosis, and cardiac muscle contraction, were differently expressed in the cardiac tissue according to the cumulative dose. Subclinical cardiac dysfunction occurs in a dose-dependent manner as detected by molecular changes in cardiac tissue, a predictor of the severity of global longitudinal strain impairment. Moreover, there was no dose threshold below which no myocardial deformation impairment was detected. Our findings i) contribute to developing new markers and exploring non-invasive magnetic resonance imaging to assess cardiac tissue changes as an early predictor of cardiac dysfunction; ii) should raise red flags, since there is no dose threshold below which no myocardial deformation impairment was detected and should be considered in radiation-based imaging and -guided therapeutic cardiac procedures; and iii) highlights the need for personalized clinical approaches.

Individual Barriers to an Active Lifestyle at Older Ages Among Whitehall II Study Participants After 20 Years of Follow-up.

Importance: Identification of individual-level barriers associated with decreased activity in older age is essential to inform effective strategies for preventing the health outcomes associated with high sedentary behavior and lack of physical activity during aging. Objective: To assess cross-sectional and prospective associations of a large set of factors with objectively assessed sedentary time and physical activity at older age. Design, Setting, and Participants: This population-based cohort study was conducted among participants in the Whitehall II accelerometer substudy with accelerometer data assessed in 2012 to 2013. Among 4880 participants invited to the accelerometer substudy, 4006 individuals had valid accelerometer data. Among them, 3808 participants also had factors assessed in 1991 to 1993 (mean [SD] follow-up time, 20.3 [0.5] years), 3782 participants had factors assessed in 2002 to 2004 (mean [SD] follow-up time, 9.1 [0.3] years), and 3896 participants had factors assessed in 2012 to 2013 (mean follow up time, 0 years). Data were analyzed from May 2020 through July 2021. Exposures: Sociodemographic factors (ie, age, sex, race and ethnicity, occupational position, and marital status), behavioral factors (ie, smoking, alcohol intake, and fruit and vegetable intake), and health-related factors (ie, body mass index, 36-Item Short Form Health Survey (SF-36) physical and mental component summary scores [PCS and MCS], and number of chronic conditions) were assessed among 3808 individuals in 1991 to 1993; 3782 individuals in 2002 to 2004; and 3896 individuals in 2012 to 2013. High alcohol intake was defined as more than 14 units of alcohol per week, and high fruit and vegetable intake was defined as twice daily or more. Main Outcomes and Measures: Accelerometer-assessed time spent in sedentary behavior, light-intensity physical activity (LIPA), and moderate to vigorous physical activity (MVPA) in 2012 to 2013 were analyzed in 2021 using multivariate linear regressions. Results: A total of 3896 participants (986 [25.3%] women; age range, 60-83 years; mean [SD] age, 69.4 [5.7] years) had accelerometer data and exposure factors available in 2012 to 2013. Older age, not being married or cohabiting, having overweight, having obesity, more chronic conditions, and poorer SF-36 PCS, assessed in midlife or later life, were associated with increased sedentary time at the expense of time in physical activity. Mean time differences ranged from 9.8 min/d (95% CI, 4.1 to 15.6 min/d) of sedentary behavior per 10-point decrease in SF-36 PCS to 51.4 min/d (95% CI, 37.2 to65.7 min/d) of sedentary behavior for obesity vs reference range weight, from -6.2 min/d (95% CI, -8.4 to -4.1 min/d) of LIPA per 5 years of age to -28.0 min/d (95% CI, -38.6 to -17.4 min/d) of LIPA for obesity vs reference range weight, and from -5.3 min/d (95% CI, -8.2 to -2.4 min/d) of MVPA per new chronic condition to -23.4 min/d (95% CI, -29.2 to -17.6 min/d) of MVPA for obesity vs reference range weight in 20-year prospective analyses for men. There was also evidence of clustering of behavioral factors: high alcohol intake, high fruit and vegetable consumption, and no current smoking were associated with decreased sedentary time (mean time difference in cross-sectional analysis in men: -12.7 min/d [95% CI, -19.8 to -5.5 min/d]; -6.0 min/d [95% CI, -12.3 to -0.2]; and -37.4 min/d [95% CI, - 56.0 to -18.8 min/d], respectively) and more physical activity. Conclusions and Relevance: This study found a large range of individual-level barriers associated with a less active lifestyle in older age, including sociodemographic, behavioral, and health-related factors. These barriers were already evident in midlife, suggesting the importance of early implementation of targeted interventions to promote physical activity and reduce sedentary time.

3-T MR neurography of lumbo-sacral plexus in hereditary transthyretin-related amyloidosis with polyneuropathy.

OBJECTIVES: Our aim was to evaluate the ability of magnetic resonance neurography (MRN) of the lumbo-sacral plexus (LSP) to distinguish patients with hereditary transthyretin-related amyloidosis with polyneuropathy (ATTRv-PN) from asymptomatic variant carriers (AVC) and healthy controls and to assess its prognostic value. METHODS: Three-Tesla MRN was performed in 25 consecutive ATTRv-PN patients, 18 AVC, and 10 controls including T2-w DIXON and DWI MR sequences. Two blinded readers independently assessed LSP root diameter and intraneural signal on the MRN images of each subject. MRN findings were compared between groups and correlated with clinical impairment scored on the Neuropathy Impairment Score (NIS) and the modified Polyneuropathy Disability score (mPND). RESULTS: The agreement between readers on MRN images was excellent (Cohen's kappa = 0.82). LSP root enlargement was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 4.38, p = 0.038). Increased LSP root intraneural signal on T2-w images was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 3.4, p = 0.016). In contrast, there were no MRN abnormalities in controls. In ATTRv-PN patients, LSP root enlargement was associated with higher mPND scores (p = 0.03) and increased intraneural signal on T2-w images was associated with significantly higher NIS and mPND scores (p = 0.004 and 0.02, respectively). CONCLUSIONS: MRN of the LSP can help differentiate ATTRv-PN patients from AVC. LSP root enlargement and increased intraneural signal are significantly associated with clinical impairment, suggesting potential implications for patient care. KEY POINTS: • ATTRv-PN patients showed abnormal LSP changes on MRN. • MRN of the LSP can help to differentiate ATTRv-PN patients from AVC and healthy controls. • LSP root enlargement and increased intraneural signal were significantly associated with clinical impairment in ATTRv-PN patients.

Deep models of integrated multiscale molecular data decipher the endothelial cell response to ionizing radiation.

The vascular endothelium is a hot spot in the response to radiation therapy for both tumors and normal tissues. To improve patient outcomes, interpretable systemic hypotheses are needed to help radiobiologists and radiation oncologists propose endothelial targets that could protect normal tissues from the adverse effects of radiation therapy and/or enhance its antitumor potential. To this end, we captured the kinetics of multi-omics layers-i.e. miRNome, targeted transcriptome, proteome, and metabolome-in irradiated primary human endothelial cells cultured in vitro. We then designed a strategy of deep learning as in convolutional graph networks that facilitates unsupervised high-level feature extraction of important omics data to learn how ionizing radiation-induced endothelial dysfunction may evolve over time. Last, we present experimental data showing that some of the features identified using our approach are involved in the alteration of angiogenesis by ionizing radiation.

Protection and safety of a repeated dosage of KI for iodine thyroid blocking during pregnancy.

In case of nuclear power plant accidents resulting in the release of radioactive iodine (131I) in large amounts, a single intake of stable iodine is recommended in order to prevent131I fixation to the thyroid gland. However, in situations of prolonged exposure to131I (e.g. Fukushima-Daiichi natural and nuclear disaster), repetitive administration of iodine may be necessary to ensure adequate protection, with acceptable safety in vulnerable populations including pregnant women. Here we conducted toxicological studies on adult rats progeny following prolonged exposure to potassium iodide (KI)in utero. Pregnant Wistar rats were treated with 1 mg kg d-1KI or saline water for 2 or 4 d either between gestation days gestational day (GD) GD 9-12, or GD13-16. Plasma samples from the progeny were tested 30 d post-weaning for clinical biochemistry, thyroid hormones, and anti-thyroid antibody levels. Thyroid and brain were collected for gene expression analysis. The hormonal status was similar for the mothers in all experimental conditions. In the offspring, while thyroid-stimulating hormone and anti-thyroid peroxidase (anti-TPO) antibody levels were similar in all groups, a significant increase of FT3 and FT4 levels was observed in GD9-GD10 and in GD13-GD14 animals treated for 2 d, respectively. In addition, FT4 levels were mildly decreased in 4 d treated GD13-16 individuals. Moreover, a significant decrease in the expression level of thyroid genes involved in iodide metabolism, TPO and apical iodide transporter, was observed in GD13-GD14 animals treated for 2 d. We conclude that repeated KI administration for 2-4 d during gestation did not induce strong thyroid toxicity.

Deciphering the Dynamic Molecular Program of Radiation-Induced Endothelial Senescence.

PURPOSE: Radiation-induced cellular senescence is a double-edged sword, acting as both a tumor suppression process limiting tumor proliferation, and a crucial process contributing to normal tissue injury. Endothelial cells play a role in normal tissue injury after radiation therapy. Recently, a study observed an accumulation of senescent endothelial cells (ECs) around radiation-induced lung focal lesions following stereotactic radiation injury in mice. However, the effect of radiation on EC senescence remains unclear because it depends on dose and fractionation, and because the senescent phenotype is heterogeneous and dynamic. METHODS AND MATERIALS: Using a systems biology approach in vitro, we deciphered the dynamic senescence-associated transcriptional program induced by irradiation. RESULTS: Flow cytometry and single-cell RNA sequencing experiments revealed the heterogeneous senescent status of irradiated ECs and allowed to deciphered the molecular program involved in this status. We identified the Interleukin-1 signaling pathway as a key player in the radiation-induced premature senescence of ECs, as well as the endothelial-to-mesenchymal transition process, which shares strong hallmarks of senescence. CONCLUSIONS: Our work provides crucial information on the dynamics of the radiation-induced premature senescence process, the effect of the radiation dose, as well as the molecular program involved in the heterogeneous senescent status of ECs.

Dosimetric study between a single isocenter dynamic conformal arc therapy technique and Gamma Knife radiosurgery for multiple brain metastases treatment: impact of target volume geometrical characteristics.

PURPOSE: To compare linac-based mono-isocentric radiosurgery with Brainlab Elements Multiple Brain Mets (MBM) SRS and the Gamma Knife using a specific statistical method and to analyze the dosimetric impact of the target volume geometric characteristics. A dose fall-off analysis allowed to evaluate the Gradient Index relevancy for the dose spillage characterization. MATERIAL AND METHODS: Treatments were planned on twenty patients with three to nine brain metastases with MBM 2.0 and GammaPlan 11.0. Ninety-five metastases ranging from 0.02 to 9.61 cc were included. Paddick Index (PI), Gradient Index (GI), dose fall-off, volume of healthy brain receiving more than 12 Gy (V12Gy) and DVH were used for the plan comparison according to target volume, major axis diameter and Sphericity Index (SI). The multivariate regression approach allowed to analyze the impact of each geometric characteristic keeping all the others unchanged. A parallel study was led to evaluate the impact of the isodose line (IDL) prescription on the MBM plan quality. RESULTS: For mono-isocentric linac-based radiosurgery, the IDL around 70-75% was the best compromise found. For both techniques, the GI and the dose fall-off decreased with the target volume. In comparison, PI was slightly improved with MBM for targets < 1 cc or SI > 0.78. GI was improved with GP for targets < 2.5 cc. The V12Gy was higher with MBM for lesions > 0.4 cc or SI < 0.84 and exceeded 10 cc for targets > 5 cc against 6.5 cc with GP. The presence of OAR close to the PTV had no impact on the dose fall off values. The dose fall-off was higher for volumes < 3.8 cc with GP which had the sharpest dose fall-off in the infero-superior direction up to 30%/mm. The mean beam-on time was 94 min with GP against 13 min with MBM. CONCLUSIONS: The dose fall-off and the V12Gy were more relevant indicators than the GI for the low dose spillage assessment. Both evaluated techniques have comparable plan qualities with a slightly improved selectivity with MBM for smaller lesions but with a healthy tissues sparing slightly favorable to GP at the expense of a considerably longer irradiation time. However, a higher healthy tissue exposure must be considered for large volumes in MBM plans.

Radiation-induced lens opacities: Epidemiological, clinical and experimental evidence, methodological issues, research gaps and strategy.

In 2011, the International Commission on Radiological Protection (ICRP) recommended reducing the occupational equivalent dose limit for the lens of the eye from 150 mSv/year to 20 mSv/year, averaged over five years, with no single year exceeding 50 mSv. With this recommendation, several important assumptions were made, such as lack of dose rate effect, classification of cataracts as a tissue reaction with a dose threshold at 0.5 Gy, and progression of minor opacities into vision-impairing cataracts. However, although new dose thresholds and occupational dose limits have been set for radiation-induced cataract, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological and mechanistic evidence at doses under 2 Gy. Since the release of the 2011 ICRP statement, the Multidisciplinary European Low Dose Initiative (MELODI) supported in April 2019 a scientific workshop that aimed to review epidemiological, clinical and biological evidence for radiation-induced cataracts. The purpose of this article is to present and discuss recent related epidemiological and clinical studies, ophthalmic examination techniques, biological and mechanistic knowledge, and to identify research gaps, towards the implementation of a research strategy for future studies on radiation-induced lens opacities. The authors recommend particularly to study the effect of ionizing radiation on the lens in the context of the wider, systemic effects, including in the retina, brain and other organs, and as such cataract is recommended to be studied as part of larger scale programs focused on multiple radiation health effects.

Extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome.

BACKGROUND: Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss, and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. METHODS: Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24, and 48 h after lethal whole-body irradiation (10 Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3), and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. RESULTS: We demonstrated that MSC-derived extracellular vesicle treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Gy whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. CONCLUSIONS: MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.

Effects of repetitive Iodine thyroid blocking on the foetal brain and thyroid in rats: a systems biology approach.

A single administration of an iodine thyroid blocking agent is usually sufficient to protect thyroid from radioactive iodine and prevent thyroid cancer. Repeated administration of stable iodine (rKI) may be necessary during prolonged or repeated exposure to radioactive iodine. We previously showed that rKI for eight days offers protection without toxic effects in adult rats. However, the effect of rKI administration in the developing foetus is unknown, especially on brain development, although a correlation between impaired maternal thyroid status and a decrease in intelligence quotient of the progeny has been observed. This study revealed distinct gene expression profiles between the progeny of rats receiving either rKI or saline during pregnancy. To understand the implication of these differentially expressed (DE) genes, a systems biology approach was used to construct networks for each organ using three different techniques: Bayesian statistics, sPLS-DA and manual construction of a Process Descriptive (PD) network. The PD network showed DE genes from both organs participating in the same cellular processes that affect mitophagy and neuronal outgrowth. This work may help to evaluate the doctrine for using rKI in case of repetitive or prolonged exposure to radioactive particles upon nuclear accidents.

Stereotactic Lung Irradiation in Mice Promotes Long-Term Senescence and Lung Injury.

PURPOSE: Lung cancer will be treated more frequently using stereotactic body radiation therapy, and preclinical research to model long-term toxicity of ablative doses of radiation is crucial. Stereotactic lung irradiation of a small volume can induce radiation pneumonitis and fibrosis in normal tissues. METHODS AND MATERIALS: Senescence has been reported to contribute to lung fibrosis, and we investigated in vivo the effects of ablative doses of ionizing radiation on senescence-associated processes. The left lung of p16INK4a-LUC knock-in mice was exposed to a single dose or fractionated radiation doses in a millimetric volume using a small animal radiation research platform. RESULTS: Single or fractionated ablative radiation induces acute and very long-term p16INK4a activation in the irradiated lung target volume associated with lung injury. We observed a panel of heterogeneous senescent cells including pneumocytes, macrophages, and endothelial cells that accumulated around the radiation-induced lung focal lesion, suggesting that different senescent cell types may contribute to radiation injury. CONCLUSIONS: This work provides important information on the long-term effects of ablative radiation doses in the normal lung and strongly suggests that stress-induced senescence is involved in stereotactic body radiation therapy-induced late fibrosis.

The association between accelerometer-assessed physical activity and respiratory function in older adults differs between smokers and non-smokers.

The association between physical activity and lung function is thought to depend on smoking history but most previous research uses self-reported measures of physical activity. This cross-sectional study investigates whether the association between accelerometer-derived physical activity and lung function in older adults differs by smoking history. The sample comprised 3063 participants (age = 60-83 years) who wore an accelerometer during 9 days and undertook respiratory function tests. Forced vital capacity (FVC) was associated with moderate-to-vigorous physical activity (MVPA; acceleration ≥0.1 g (gravity)) in smokers but not in never smokers: FVC differences for 10 min increase in MVPA were 58.6 (95% Confidence interval: 21.1, 96.1), 27.8 (4.9, 50.7), 16.6 (7.9, 25.4), 2.8 (-5.2, 10.7) ml in current, recent ex-, long-term ex-, and never-smokers, respectively. A similar trend was observed for forced expiratory volume in 1 second. Functional data analysis, a threshold-free approach using the entire accelerometry distribution, showed an association between physical activity and lung function in all smoking groups, with stronger association in current and recent ex-smokers than in long-term ex- and never-smokers; the associations were evident in never smokers only at activity levels above the conventional 0.1 g MVPA threshold. These findings suggest that the association between lung function and physical activity in older adults is more pronounced in smokers than non-smokers.

From Energy Deposition of Ionizing Radiation to Cell Damage Signaling: Benchmarking Simulations by Measured Yields of Initial DNA Damage after Ion Microbeam Irradiation.

Advances in accelerator technology, which have enabled conforming radiotherapy with charged hadronic species, have brought benefits as well as potential new risks to patients. To better understand the effects of ionizing radiation on tumor and surrounding tissue, it is important to investigate and quantify the relationship between energy deposition at the nanometric scale and the initial biological events. Monte Carlo track structure simulation codes provide a powerful tool for investigating this relationship; however, their success and reliability are dependent on their improvement and development accordingly to the dedicated biological data to which they are challenged. For this aim, a microbeam facility that allows for fluence control, down to one ion per cell nucleus, was used to evaluate relative frequencies of DNA damage after interaction between the incoming ion and DNA according to radiation quality. Primary human cells were exposed to alpha particles of three different energies with respective linear energy transfers (LETs) of approximately 36, 85 or 170 keV·µm-1 at the cells' center position, or to protons (19 keV·µm-1). Statistical evaluation of nuclear foci formation (53BP1/γ-H2AX), observed using immunofluorescence and related to a particle traversal, was undertaken in a large population of cell nuclei. The biological results were adjusted to consider the factors that drive the experimental uncertainties, then challenged with results using Geant4-DNA code modeling of the ionizing particle interactions on a virtual phantom of the cell nucleus with the same mean geometry and DNA density as the cells used in our experiments. Both results showed an increase of relative frequencies of foci (or simulated DNA damage) in cell nuclei as a function of increasing LET of the traversing particles, reaching a quasi-plateau when the LET exceeded 80-90 keV·µm-1. For the LET of an alpha particle ranging from 80-90 to 170 keV·µm-1, 10-30% of the particle hits did not lead to DNA damage inducing 53BP1 or γ-H2AX foci formation.

Heparan Sulfate Mimetics: A New Way to Optimize Therapeutic Effects of Hydrogel-Embedded Mesenchymal Stromal Cells in Colonic Radiation-Induced Damage.

Clinical expression of gastrointestinal radiation toxicity on non-cancerous tissue could be very life threatening and clinicians must deal increasingly with the management of late side effects of radiotherapy. Cell therapy, in particular mesenchymal stromal cell (MSC) therapy, has shown promising results in numerous preclinical animal studies and thus has emerged as a new hope for patient refractory to current treatments. However, many stem cell clinical trials do not confer any beneficial effect suggesting a real need to accelerate research towards the successful clinical application of stem cell therapy. In this study, we propose a new concept to improve the procedure of MSC-based treatment for greater efficacy and clinical translatability. We demonstrated that heparan sulfate mimetic (HS-m) injections that restore the extracellular matrix network and enhance the biological activity of growth factors, associated with local injection of MSC protected in a hydrogel, that increase cell engraftment and cell survival, improve the therapeutic benefit of MSC treatment in two animal models relevant of the human pathology. For the first time, a decrease of the injury score in the ulcerated area was observed with this combined treatment. We also demonstrated that the combined treatment favored the epithelial regenerative process. In this study, we identified a new way, clinically applicable, to optimize stem-cell therapy and could be proposed to patients suffering from severe colonic defect after radiotherapy.

Temporal clustering analysis of endothelial cell gene expression following exposure to a conventional radiotherapy dose fraction using Gaussian process clustering.

The vascular endothelium is considered as a key cell compartment for the response to ionizing radiation of normal tissues and tumors, and as a promising target to improve the differential effect of radiotherapy in the future. Following radiation exposure, the global endothelial cell response covers a wide range of gene, miRNA, protein and metabolite expression modifications. Changes occur at the transcriptional, translational and post-translational levels and impact cell phenotype as well as the microenvironment by the production and secretion of soluble factors such as reactive oxygen species, chemokines, cytokines and growth factors. These radiation-induced dynamic modifications of molecular networks may control the endothelial cell phenotype and govern recruitment of immune cells, stressing the importance of clearly understanding the mechanisms which underlie these temporal processes. A wide variety of time series data is commonly used in bioinformatics studies, including gene expression, protein concentrations and metabolomics data. The use of clustering of these data is still an unclear problem. Here, we introduce kernels between Gaussian processes modeling time series, and subsequently introduce a spectral clustering algorithm. We apply the methods to the study of human primary endothelial cells (HUVECs) exposed to a radiotherapy dose fraction (2 Gy). Time windows of differential expressions of 301 genes involved in key cellular processes such as angiogenesis, inflammation, apoptosis, immune response and protein kinase were determined from 12 hours to 3 weeks post-irradiation. Then, 43 temporal clusters corresponding to profiles of similar expressions, including 49 genes out of 301 initially measured, were generated according to the proposed method. Forty-seven transcription factors (TFs) responsible for the expression of clusters of genes were predicted from sequence regulatory elements using the MotifMap system. Their temporal profiles of occurrences were established and clustered. Dynamic network interactions and molecular pathways of TFs and differential genes were finally explored, revealing key node genes and putative important cellular processes involved in tissue infiltration by immune cells following exposure to a radiotherapy dose fraction.