scholarly journals Relative biological effect of alpha particle radiation on low dose phenomena: lethal mutation, hyper-radiosensitivity and increased radioresistance

2018 ◽  
Author(s):  
Chandula Fernando ◽  
Xiaopei Shi ◽  
Soo Hyun Byun ◽  
Colin B. Seymour ◽  
Carmel E. Mothersill
Keyword(s):  
Gamma Radiation ◽  
Cell Line ◽  
Biological Effect ◽  
Low Dose ◽  
Alpha Particles ◽  
Common Source ◽  
Low Doses ◽  
Gamma Energy ◽  
Weighting Factors ◽  
Increased Radioresistance

AbstractAt high doses, the current recommended radiation weighting factors advise a significantly higher effectiveness of alpha particles relative to gamma radiation. However, at lower doses, the ratio of effectiveness between radiations of varying linear energy transfer values is complicated due to the relative importance of low dose phenomena such as genomic instability, bystander effects, low dose hyper-radiosensitivity and increased radioresistance (HRS/IRR). Radium is the most common source of alpha radiation exposure to humans, but the dosimetry is complicated by the decay chain which involves gamma exposure due to radon daughters. This study aimed to isolate the relative biological effect of alpha particles after low doses of radium to cells and their progeny. This was done by subtracting the survival values of a human keratinocyte cell line (HaCaT) and an embryonic Chinook salmon cell line (CHSE-214) exposed to gamma irradiation, from survival of the same cell lines exposed to mixed alpha and gamma radiation through chronic exposure to Ra-226 and its decay products. The human cell line showed increased radioresistance when exposed to low doses of alpha particles. In contrast the fish cell line, which demonstrated radioresistance to low dose gamma energy, demonstrated increased lethality when exposed to low doses of alpha particles. The results confirm the need to consider the dose-response relationship when developing radiation weighting factors for low dose exposures, as well as the need to be aware of possible cell line and species differences.

scholarly journals Induction of Genomic Instability in a Primary Human Fibroblast Cell Line Following Low-Dose Alpha-Particle Exposure and the Potential Role of Exosomes

Biology ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 11
Author(s):  
Eman Mohammed Elbakrawy ◽  
Ammar Mayah ◽  
Mark A. Hill ◽  
Munira Kadhim
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Alpha Particle ◽  
Low Dose ◽  
Potential Role ◽  
Alpha Particles ◽  
Low Doses ◽  
Particle Exposure ◽  
Population Doublings

Purpose: To study the induction of genomic instability (GI) in the progeny of cell populations irradiated with low doses of alpha-particles and the potential role of exosome-encapsulated bystander signalling. Methods: The induction of GI in HF19 normal fibroblast cells was assessed by determining the formation of micronuclei (MN) in binucleate cells along with using the alkaline comet assay to assess DNA damage. Results: Low dose alpha-particle exposure (0.0001–1 Gy) was observed to produce a significant induction of micronuclei and DNA damage shortly after irradiation (assays performed at 5 and 1 h post exposure, respectively). This damage was not only still evident and statistically significant in all irradiated groups after 10 population doublings, but similar trends were observed after 20 population doublings. Exosomes from irradiated cells were also observed to enhance the level of DNA damage in non-irradiated bystander cells at early times. Conclusion: very low doses of alpha-particles are capable of inducing GI in the progeny of irradiated cells even at doses where <1% of the cells are traversed, where the level of response was similar to that observed at doses where 100% of the cells were traversed. This may have important implications with respect to the evaluation of cancer risk associated with very low-dose alpha-particle exposure and deviation from a linear dose response.

Study of Heptamethine Iodide and Heptamethine PF6 Solutions in Different Solvents for the Measurement of Low Doses of X-Ray & Gamma Radiation

2016 ◽  
Vol 5 (4) ◽  
pp. 308-317
Author(s):  
Hagos Tesfay ◽  
Erika S. Bronze-Uhle ◽  
Augusto Batagin-Neto ◽  
Anna C. Véron ◽  
Thomas Geiger ◽  
...  
Keyword(s):  
Gamma Radiation ◽  
Low Doses ◽  
X Ray

scholarly journals AB1335-HPR HEALTH PROFESSIONALS’ PERSPECTIVE ON THE BENEFITS AND RISKS OF LOW-DOSE GLUCOCORTICOIDS IN RHEUMATOID ARTHRITIS – AN INTERNATIONAL SURVEY OF 444 HEALTH PROFESSIONALS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1955.1-1956
Author(s):  
T. Santiago ◽  
M. Voshaar ◽  
M. De Wit ◽  
P. Carvalho ◽  
M. Boers ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Events ◽  
Health Professionals ◽  
Patient Perspective ◽  
Online Survey ◽  
Low Dose ◽  
Low Doses ◽  
Research Support ◽  
Serious Adverse Events ◽  
Patient Organizations

Background:The Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis Study (GLORIA) is an international investigator-initiated pragmatic randomized trial designed to study the effects of low-dose glucocorticoids (GCs) in elderly patients with Rheumatoid Arthritis (RA).The research team is also committed to promote a better understanding of the risks and benefits of these drugs among health professionals and patients. In order to achieve these goals, it is important to assess the current ideas and concerns of patients regarding GCs.Objectives:To evaluate the current patient perspective on the efficacy and risks of GCs in RA patients who are or have been treated with GCs.Methods:Patients with RA completed an online survey (with 5 closed questions regarding efficacy and safety) presented in their native language. RA patients were recruited through a variety of patient organizations representing three continents. Patients were invited to participate through national patient organizations. In the USA, patients were also invited to participate through MediGuard.org. Participants were asked for their level of agreement on a 5-point Likert scale.Results:1344 RA patients with exposure to GCs, from Brazil, USA, UK, Portugal, Netherlands, Germany and 24 other countries** participated: 89% female, mean age (SD) 52 (14) years and mean disease duration 13 (11) years. The majority of participants (84%) had ≥10 years of education. The duration of GCs exposure was 1.6 (4.2) years. The majority of participants had read articles or pamphlets on the benefits or harms of GC therapy.Regarding GCs efficacy (table 1), high levels of endorsement were found: about 2/3 of patients considered that GCs as very useful in their case, more than half considered that GCs were effective even at low doses, and agreed that GC improved RA symptoms within days.Regarding safety (table 1), 1/3 of the participants reported having suffered some form of serious adverse events (AEs) due to GCs, and 9% perceived this as “life-threatening. Adverse events had a serious impact on quality of life, according to about 1/3 of the respondents.Conclusion:Patients with RA exposed to GC report a strong conviction that GCs are very useful and effective for the treatment of their RA, even at low doses. This is accompanied by an important prevalence of serious AEs. Understanding the patient perspective can improve shared decision-making between patient and rheumatologist.Funding statement:This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634886.Disclosure of Interests:Tânia Santiago: None declared, Marieke Voshaar Grant/research support from: part of phd research, Speakers bureau: conducting a workshop (Pfizer), Maarten de Wit Grant/research support from: Dr. de Wit reports personal fees from Ely Lilly, 2019, personal fees from Celgene, 2019, personal fees from Pfizer, 2019, personal fees from Janssen-Cilag, 2017, outside the submitted work., Consultant of: Dr. de Wit reports personal fees from Ely Lilly, 2019, personal fees from Celgene, 2019, personal fees from Pfizer, 2019, personal fees from Janssen-Cilag, 2017, outside the submitted work., Speakers bureau: Dr. de Wit reports personal fees from Ely Lilly, 2019, personal fees from Celgene, 2019, personal fees from Pfizer, 2019, personal fees from Janssen-Cilag, 2017, outside the submitted work., Pedro Carvalho: None declared, Maarten Boers: None declared, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis

scholarly journals Sorafenib is a potent inhibitor of FIP1L1-PDGFRα and the imatinib-resistant FIP1L1-PDGFRα T674I mutant

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1374-1376 ◽  
Author(s):  
Els Lierman ◽  
Cedric Folens ◽  
Elizabeth H. Stover ◽  
Nicole Mentens ◽  
Helen Van Miegroet ◽  
...  
Keyword(s):  
Low Dose ◽  
Potent Inhibitor ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Low Doses ◽  
Chronic Eosinophilic Leukemia ◽  
Nanomolar Concentration ◽  
Imatinib Resistant ◽  
Factor Receptor Alpha ◽  
Induced Apoptosis

Abstract The FIP1L1-PDGFRA oncogene is a common cause of chronic eosinophilic leukemia (CEL), and encodes an activated tyrosine kinase that is inhibited by imatinib. FIP1L1-PDGFRA–positive patients with CEL respond to low-dose imatinib therapy, but resistance due to acquired T674I mutation has been observed. We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1–platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) (T674I) mutant. Sorafenib inhibited the proliferation of FIP1L1-PDGFRα and FIP1L1-PDGFRα(T674I)–transformed Ba/F3 cells and induced apoptosis of the EOL-1 cell line at a low nanomolar concentration. Western blot analysis confirmed that these effects were due to a direct effect on FIP1L1-PDGFRα and FIP1L1-PDGFRα(T674I). Sorafenib was recently approved for the treatment of renal cell carcinoma. Our data suggest that low doses of sorafenib could be efficient for the treatment of FIP1L1-PDGFRA–positive CEL and could be used to overcome resistance to imatinib associated with the T674I mutation.

Thiamme2-G, A Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice

2021 ◽  
pp. 1-14
Author(s):  
Danmin Pan ◽  
Jin-Hua Gu ◽  
Jin Zhang ◽  
Yae Hu ◽  
Fei Liu ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Low Dose ◽  
Body Weight Loss ◽  
Synaptic Proteins ◽  
Novel Object Recognition ◽  
Low Doses ◽  
Tau Hyperphosphorylation ◽  
Protein Tau ◽  
Abnormal Hyperphosphorylation ◽  
Brain Changes

Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer’s disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). Methods: STZ was injected into the lateral ventricle of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. Results: ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. Conclusion: These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD.

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