Radiation Hormesis in Barley Manifests as Changes in Growth Dynamics Coordinated with the Expression of PM19L-like, CML31-like, and AOS2-like.

The stimulation of growth and development of crops using ionising radiation (radiation hormesis) has been reported by many research groups. However, specific genes contributing to the radiation stimulation of plant growth are largely unknown. In this work, we studied the impact of the low-dose γ-irradiation of barley seeds on the growth dynamics and gene expression of eight barley cultivars in a greenhouse experiment. Our findings confirmed that candidate genes of the radiation growth stimulation, previously established in barley seedlings (PM19L-like, CML31-like, and AOS2-like), are significant in radiation hormesis throughout ontogeny. In γ-stimulated cultivars, the expression of these genes was aligned with the growth dynamics, yield parameters, and physiological conditions of plants. We identified contrasting cultivars for future gene editing and found that the γ-stimulated cultivar possessed some specific abiotic stress-responsive elements in the promotors of candidate genes, possibly revealing a new level of radiation hormesis effect execution. These results can be used in creating new productive barley cultivars, ecological toxicology of radionuclides, and eustress biology studies.

The Dose-Dependent Effect of Fractionated γ-Radiation on Anxiety-Like Behavior in Neonatal Mice.

High doses of ionizing radiation are the risk factor of cognitive dysfunction and anxiety disorders developing in humans and experimental animals. However, the data on the effect of low doses, especially in case of chronic or fractionated exposure, is limited and contradictory. Here we studied the effect of fractionated γ-radiation at cumulative doses of 0.1, 1, and 5 Gy on the parameters of the anxiety-like behavior in neonatal C57BL/6 mice. The anxiety was evaluated using the marble burying test and elevated plus maze. Fractionated irradiation resulted in dose-dependent changes in mouse behavior: the low dose caused an increase in anxiety, wherein the dose raise led to the decrease in anxiety-like behavior indicators compared to non-irradiated animals.

Exposure to either Bisphenol A or S Represents a Risk for Crucial Behaviors for Pup Survival, Such as Spontaneous Maternal Behavior in Mice.

INTRODUCTION: Maternal behavior depends on a multitude of factors, including environmental ones, such as Endocrine Disrupting Chemicals (EDCs), which are increasingly attracting attention. Bisphenol A (BPA), an EDC present in plastic, is known to exert negative effects on maternal behavior. Bisphenol S (BPS), a BPA substitute, seems to share some endocrine disrupting properties. In this study, we focused on the analysis of the effects of low-dose (i.e., 4 µg/kg body weight/day, EFSA TDI for BPA) BPA or BPS exposure throughout pregnancy and lactation in mice. METHODS: We administered adult C57BL/6 J females orally BPA, BPS, or vehicle from mating to offspring weaning. We assessed the number of pups at birth, the sex ratio, and the percentage of dead pups in each litter, and during the first postnatal week, we observed spontaneous maternal behavior. At the weaning of the pups, we sacrificed the dams and analyzed the oxytocin system, known to be involved in the control of maternal care, in the hypothalamic magnocellular nuclei. RESULTS: At birth, pups from BPA-treated dams tended to have a lower male-to-female ratio compared to controls, while the opposite was observed among BPS-treated dams' litters. During the first postnatal week, offspring mortality impacted differentially in the BPA and BPS litters, with more female dead pups among the BPA litters, while more male dead pups in the BPS litters, sharpening the difference in the sex ratio. BPA- and BPS-treated dams spent significantly less time in pup-related behaviors than controls. Oxytocin immunoreactivity in the paraventricular and supraoptic nuclei was increased only in the BPA-treated dams. DISCUSSION/CONCLUSIONS: Alterations in maternal care, along with the treatment itself, may affect, later in life, the offspring's physiology and behavior. Exposure to BPs during sensitive developmental periods represents a risk for both dams and offspring, even at low environmentally relevant doses, through the functional alteration of neural circuits controlling fundamental behaviors for pup survival, such as maternal behaviors.

How an Immune-Factor-Based Formulation of Micro-Immunotherapy Could Interfere with the Physiological Processes Involved in the Atopic March.

Allergic diseases consist of improper inflammatory reactions to antigens and are currently an important healthcare concern, especially considering their increasing worldwide development in recent decades. The "atopic march" defines the paradigm of allergic diseases occurring in chronological order and displaying specific spatial manifestations, as they usually start as atopic dermatitis (AD) and food allergies during infancy and progressively evolve into allergic asthma (AA) and allergic rhinitis (AR) or rhino-conjunctivitis in childhood. Many immune cell subtypes and inflammatory factors are involved in these hypersensitivity reactions. In particular, the T helpers 2 (Th2) subset, through its cytokine signatures made of interleukins (ILs), such as IL-4, IL-5, IL-10, and IL-13, as well as mast cells and their related histamine pathways, contribute greatly to the perpetuation and evolution of the atopic march. By providing low doses (LD) and ultra-low doses (ULD) of ILs and immune factors to the body, micro-immunotherapy (MI) constitutes an interesting therapeutic strategy for the management of the atopic march and its symptoms. One of the aims of this review is to shed light on the current concept of the atopic march and the underlying immune reactions occurring during the IgE-mediated responses. Moreover, the different classes of traditional and innovative treatments employed in allergic diseases will also be discussed, with a special emphasis on the potential benefits of the MI medicine 2LALERG® formulation in this context.

A Sequential Micro-Immunotherapy Medicine Increases Collagen Deposition in Human Gingival Fibroblasts and in an Engineered 3D Gingival Model under Inflammatory Conditions.

Periodontal therapies use immune mediators, but their side effects can increase with dosage. Micro-immunotherapy (MI) is a promising alternative that employs immune regulators at low and ultralow doses to minimize adverse effects. In this study, the effects of 5 capsules and the entire 10-capsule sequence of the sequential MI medicine (MIM-seq) were tested in two in vitro models of periodontitis. Firstly, human gingival fibroblasts (hGFs) exposed to interleukin (IL)-1ß to induce inflammation were treated with five different capsules of MIM-seq for 3 days or with MIM-seq for 24 days. Subsequently, MIM-seq was analyzed in a 3D model of human tissue equivalent of gingiva (GTE) under the same inflammatory stimulus. Simultaneously, a non-IL-1ß-treated control and a vehicle were included. The effects of the treatments on cytotoxicity, collagen deposition, and the secreted levels of IL-1α, IL-6, prostaglandin E2 (PGE2), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were evaluated. None of the tested items were cytotoxic. The complete sequence of MIM-seq decreased PGE2 release and restored collagen deposition levels induced by IL-1ß treatment in hGFs exposed to IL-1ß. MIM-seq treatment restored collagen production levels in both models. These promising preclinical findings suggest that MIM-seq should be further investigated for periodontitis treatment.

Assessment of Ante- and Postnatal Development of the Offspring of Male Rats Crossed in Delayed Periods after Treatment with Methotrexate in Low Doses.

We studied ante- and postnatal development of the offspring of intact female rats crossed with males injected with low doses of methotrexate 3 and 6 months before mating. The time of crossing corresponded to the manifestation of the cytostatic effect on spermatogonial stem cells. The offspring of methotrexate-treated males was characterized by increased preimplantation losses and fetal growth restriction in the antenatal period and inhibition of physical development, delayed formation of sensory-motor reflexes, and impaired learning abilities in the postnatal period.

[Correlation analysis and benchmark dose study on bone metabolic biochemical index of low doses of exposed hydrogen fluoride workers].

Objective: To analyze correlation of occupational hydrogen fluoride exposure to low doses of bone metabolism index through occupational epidemiological investigation and benchmark dose calculation. Methods: In May 2021, using cluster sampling method, 237 workers exposed to hydrogen fluoride in a company were selected as the contact group, and 83 workers not exposed to hydrogen fluoride in an electronics production company were selected as the control group. The external exposure dose and urinary fluoride concentration, blood and urine biochemical indicators of the workers was measured.The relationship between external dose and internal dose of hydrogen fluoride was analyzed. The external dose, urinary fluoride was used as exposure biomarkers, while serum osteocalcin (BGP), serum alkaline phosphatase (AKP) and urinary hydroxyproline (HYP) were used as effect biomarkers for bone metabolism of hydrogen fluoride exposure. The benchmark dose calculation software (BMDS1.3.2) was used to calculate benchmark dose (BMD) . Results: Urine fluoride concentration in the contact group was correlated with creatinine-adjusted urine fluoride concentration (r=0.69, P=0.001). There was no significant correlation between the external dose of hydrogen fluoride and urine fluoride in the contact group (r=0.03, P=0.132). The concentrations of urine fluoride in the contact group and the control group were (0.81±0.61) and (0.45±0.14) mg/L, respectively, and the difference between the two groups was statistically significant (t=5.01, P=0.025). Using BGP, AKP and HYP as effect indexes, the urinary BMDL-05 values were 1.28, 1.47 and 1.08 mg/L, respectively. Conclusion: Urinary fluoride can sensitively reflect the changes in the effect indexes of biochemical indexes of bone metabolism. BGP and HYP can be used as early sensitive effect indexes of occupational hydrogen fluoride exposure.

Improving control of high-grade glioma by ultra-hyper-fractionated radiotherapy.

Ionizing radiation is a mainstay of high-grade glioma therapy. The current standard radiotherapeutic schedule involves a total 60 Gy split in 2.0 Gy fractions delivered on weekdays for six weeks. Thereafter, almost invariably the tumor relapses and progresses. In vitro studies have demonstrated that the therapeutic effectiveness of ionizing radiation towards high-grade glioma cells is greatly increased by splitting the total dose in fractions ten times smaller [0.1-0.5 Gy instead of standard 2.0 Gy-ultra-hyper-fractionated radiotherapy (ultra-hyper-FRT)]. Recently, it became possible to consistently translate this therapeutic effect to the animal setting, by using glioma-initiating cell-driven faithful animal modeling. A re-analysis of the literature reporting radiotherapeutic clinical trials also suggests that the lower the average fraction size, the higher is the achievable overall survival of patients. However, average fraction sizes ≤ 0.5 Gy have never been thoroughly investigated in the clinics. We propose to study in the clinical setting the therapeutic effect of an ultra-hyper-FRT schedule promptly extending the conventional radiation component of the current guidelines ("Stupp") therapeutic protocol.

Reflections on effects of low doses and risk inference based on the UNSCEAR 2021 report on 'biological mechanisms relevant for the inference of cancer risks from low-dose and low-dose-rate radiation'.

The 2021 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) report summarises the knowledge on biological mechanisms of radiation action at low doses where, due to low statistical power of epidemiological investigations, the level of cancer risk must be inferred. It is the fourth UNSCEAR report since 1994 that looks into biological effects following low dose exposure with the aim of examining whether they support the assumption of the linear non-threshold (LNT) dose response for radiation-induced cancers. The conclusions of all four reports are affirmative. The new aspect of the 2021 report is that it focuses on the process of cancer risk inference. The aim of this article is to discuss the consequences of the conclusions regarding LNT and the possibilities of inferring risks from biological studies.

Treatment of benign tumours and related pathologies with radiotherapy: experience of the General Hospital of Mexico.

Background: Benign diseases include tumours or localized growths with low potential for progression. The use of radiotherapy (RT) at a low dose (LD) or intermediate dose for benign pathologies has been widely proposed and studied. Currently, the use of RT is limited mainly to hyperproliferative and inflammatory diseases as a first or second line of treatment. Materials and methods: This was a retrospective, observational and descriptive study conducted in the Radiotherapy Unit of the Oncology Service of the General Hospital of Mexico "Dr. Eduardo Liceaga" from January 2, 2016, to December 31, 2020. Patients diagnosed with benign pathology and treated with RT were included. The response to treatment was recorded based on the imaging study report and/or clinical review that determined control of the disease, and toxicity was recorded based on the RTOG evaluation for acute effects and CTCAE V. 4.0 for chronic effects. Results: The records of 222 patients were analysed. The mean follow-up duration was 31.53 months (range 6-61), and the median was 24 months. Of all of the analysed pathologies that were treated with RT, keloid scars predominated in 112 patients (50.5%), and paragangliomas predominated in 72 patients (32.4%); the other patients were treated for rare pathologies. The prescribed dose was dependent on the diagnosis, with the mean dose being 31.63 Gy (1500-6000 cGy) and the median being 2000 cGy. Most of the cases of acute and chronic toxicity were grades 1 and 2, and a disease response was achieved in 94.1% of the patients. Conclusion: Our series shows that for cases of benign pathology, RT offers acceptable toxicity, improves quality of life and yields a good response, achieving disease control. These results suggest the inclusion of inflammatory pathology among the indications for treatment.

Evaluation of the lifetime brain/central nervous system cancer risk associated with childhood head CT scanning in Japan.

The use of computed tomography (CT) scanning has increased worldwide over the decades, and Japan is one of the leading countries in annual frequency of diagnostic CT. Although benefits of CT scan are undisputable, concerns have been raised about potential health effects of ionizing radiation exposure from CT, particularly among children who are likely more susceptible to radiation than adults. Our study aims to evaluate the cumulated lifetime risk of the brain/central nervous system (CNS) cancer due to head CT examinations performed on Japanese children at age 0 to 10 years in 2012, 2015 and 2018. The frequency and dose distribution of head CT examinations were estimated based on information from recent national statistics and nationwide surveys. The lifetime risk attributable to exposure was calculated by applying risk models based on the study of Japanese atomic-bomb survivors. In contrast to the overall increasing trend, the frequency of childhood CT, especially at age < 5, was decreasing, reflecting a growing awareness for efforts to reduce childhood CT exposure over the past decade. In 2018, 138 532 head CT examinations were performed at age 0 to 10, which would consequently induce a lifetime excess of 22 cases (1 per 6300 scans) of brain/CNS cancers, accounting for 5% of the total cases. More excess cases were estimated among men than among women, and excess cases could emerge at relatively young ages. These results would have useful implications as scientific basis for future large-scale epidemiological studies and also as quantitative evidence to justify the benefits of CT vs risks in Japan.

Ultra-Low Dose Cytokines in Rheumatoid Arthritis, Three Birds with One Stone as the Rationale of the 2LARTH® Micro-Immunotherapy Treatment.

Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH® uses ultra-low doses (ULD) of TNF-α, IL-1ß, and IL-2, in association with other immune factors, to gently restore the body's homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1ß and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1ß and TNF-α in 2LARTH® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis.

ALARA in practice-4 decades of radiological protection at Goesgen NPP.

This paper provides an overview of results achieved through a whole set of ALARA investigations at the Goesgen Nuclear Power Plant. Doses to workers, the public and the environment have significantly dropped in recent years. Even the doses to the most exposed workers at the plant are not bigger than doses from natural background radiation. Recent reviews of epidemiological data call attention to the importance of recognising that the risk of cancer at low doses is small and might contribute only a very small, non-detectable fraction to an individual's overall risk. Based on the global cultural change on how society is facing any kind of risk, the initial ALARA philosophy is moving more and more to a continuing expectation that optimisation is equivalent to reduction. This philosophy change is even more pronounced in the light of the ongoing discussions about the effects of low dose radiation. Multiple conservatisms in dose models and dose calculations will lead to an imbalance between radiation risks and benefits. Overweighting radiation risks from low doses causes anxiety among the public and unnecessary economic burden to nuclear facilities. In light of pressing global issues (i.e. climate change), a discussion about the meaning of the 'R' in ALARA is recommended.

Ionizing Radiation and Translation Control: A Link to Radiation Hormesis?

Protein synthesis, or mRNA translation, is one of the most energy-consuming functions in cells. Translation of mRNA into proteins is thus highly regulated by and integrated with upstream and downstream signaling pathways, dependent on various transacting proteins and cis-acting elements within the substrate mRNAs. Under conditions of stress, such as exposure to ionizing radiation, regulatory mechanisms reprogram protein synthesis to translate mRNAs encoding proteins that ensure proper cellular responses. Interestingly, beneficial responses to low-dose radiation exposure, known as radiation hormesis, have been described in several models, but the molecular mechanisms behind this phenomenon are largely unknown. In this review, we explore how differences in cellular responses to high- vs. low-dose ionizing radiation are realized through the modulation of molecular pathways with a particular emphasis on the regulation of mRNA translation control.

Radon Exposure-Therapeutic Effect and Cancer Risk.

Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas, contributes as the largest single fraction to radiation exposure from natural sources. For that reason, radon represents a major issue for radiation protection. Nevertheless, radon is also applied for the therapy of inflammatory and degenerative diseases in galleries and spas to many thousand patients a year. In either case, chronic environmental exposure or therapy, the effect of radon on the organism exposed is still under investigation at all levels of interaction. This includes the physical stage of diffusion and energy deposition by radioactive decay of radon and its progeny and the biological stage of initiating and propagating a physiologic response or inducing cancer after chronic exposure. The purpose of this manuscript is to comprehensively review the current knowledge of radon and its progeny on physical background, associated cancer risk and potential therapeutic effects.

Low-dose zoledronate for the treatment of bone metastasis secondary to prostate cancer.

BACKGROUND: Bisphosphonates (BPs) including zoledronate (zol) have become standard care for bone metastases as they effectively inhibit tumor-induced osteolysis and associated pain. Several studies have also suggested that zol has direct anti-tumor activity. Systemic administration at high doses is the current approach to deliver zol, yet it has been associated with debilitating side effects. Local therapeutic delivery offers the ability to administer much lower total dosage, while at the same time maintaining sustained high-local drug concentration directly at the target treatment site. Here, we aimed to assess effects of lower doses of zol on bone metastases over a longer time. METHODS: Prostate cancer cell line LAPC4 and prostate-induced bone metastasis cells were treated with zol at 1, 3 and 10 µM for 7 days. Following treatment, cell proliferation was assessed using Almarblue®, Vybrant MTT®, and Live/Dead® viability/cytotoxicity assays. Additionally, cell migration and invasion were carried out using Falcon™ cell culture inserts and Cultrex® 3D spheroid cell invasion assays respectively. RESULTS: We show that treatment with 3-10 µM zol over 7-days significantly decreased cell proliferation in both the prostate cancer cell line LAPC4 and cells from spine metastases secondary to prostate cancer. Using the same low-dose and longer time course for treatment, we demonstrate that 10 µM zol also significantly inhibits tumor cell migration and 3D-cell growth/invasion. CONCLUSIONS: This project harnesses the potential of using zol at low doses for longer treatment periods, which may be a viable treatment modality when coupled with biomaterials or biodevices for local delivery.

Educating about radiation risks in high schools: towards improved public understanding of the complexity of low-dose radiation health effects.

The levels of stochastic health effects following exposure to low doses of ionising radiation are not well known. A consequence of the uncertainty is that any radiation exposure is met with deep concern-both by the public and by scientists who disagree about how the partly conflicting results from low-dose studies should be interpreted. The concern is not limited to ionising radiation but is inherent to other areas of modern technologies such as biotechnology or electromagnetic fields. The everyday presence of advanced technologies confronts people with the necessity to take decisions and there is an ongoing debate regarding both the nature and magnitude of potential risks and how education efforts may empower peoples´ decision-making. In the field of radiation research there are different opinions regarding the optimal education methods, spanning from the idea that peoples' fears will be eliminated by introducing dose thresholds below which the risk is assumed to be zero, to suggestions of concentrating research efforts in an attempt to eliminate all uncertainties regarding the effects of low doses. The aim of this paper was to present our approach which is based on developing an education program at the secondary school level where students learn to understand the role of science in society. Teaching about radiation risk as a socio-scientific issue is not based on presenting facts but on showing risks in a broader perspective aiming at developing students' competency in making decisions based on informed assessment. We hope to stimulate and encourage other researchers to pursue similar approaches.

[Enzyme replacement therapy in adult patients with type I Gaucher disease].

Enzyme replacement therapy (ERT) is the standard for the treatment of Gaucher disease (GD). A lifelong intravenous administration of a recombinant analogue of human glucocerebrosidase compensates for the functional deficiency of its own enzyme. The use of ERT has changed the clinical phenotype of GD, a severe progressive disease has been turned into the status of an asymptomatic metabolic defect. At the same time, a reduced dosing ERT regimen applied in Gaucher patients who had achieved therapeutic goals has not yet been developed.

Nanoparticle Exposure and Hormetic Dose-Responses: An Update.

The concept of hormesis, as an adaptive response of biological systems to moderate environmental challenges, has raised considerable nano-toxicological interests in view of the rapid pace of production and application of even more innovative nanomaterials and the expected increasing likelihood of environmental and human exposure to low-dose concentrations. Therefore, the aim of this review is to provide an update of the current knowledge concerning the biphasic dose-responses induced by nanoparticle exposure. The evidence presented confirmed and extended our previous findings, showing that hormesis is a generalized adaptive response which may be further generalized to nanoscale xenobiotic challenges. Nanoparticle physico-chemical properties emerged as possible features affecting biphasic relationships, although the molecular mechanisms underlining such influences remain to be fully understood, especially in experimental settings resembling long-term and low-dose realistic environmental exposure scenarios. Further investigation is necessary to achieve helpful information for a suitable assessment of nanomaterial risks at the low-dose range for both the ecosystem function and the human health.

Risk of second cancers in the era of modern radiation therapy: does the risk/benefit analysis overcome theoretical models?

In the era of modern radiation therapy, the compromise between the reductions in deterministic radiation-induced toxicities through highly conformal devices may be impacting the stochastic risk of second malignancies. We reviewed the clinical literature and evolving theoretical models evaluating the impact of intensity-modulated radiation therapy (IMRT) on the risk of second cancers, as a consequence of the increase in volumes of normal tissues receiving low doses. The risk increase (if any) is not as high as theoretical models have predicted in adults. Moreover, the increase in out-of-field radiation doses with IMRT could be counterbalanced by the decrease in volumes receiving high doses. Clinical studies with short follow-up have not corroborated the hypothesis that IMRT would drastically increase the incidence of second cancers. In children, the risk of radiation-induced carcinogenesis increases from low doses and consequently the relative risk of second cancers after IMRT could be higher than in adults, justifying current developments of proton therapy with priority given to this population. Although only longer follow-up will allow a true assessment of the real impact of these modern techniques on radiation-induced carcinogenesis, a comprehensive risk-adapted strategy will help minimize the probability of second cancers.