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Metabolites Jun 2022High-throughput biodosimetry methods to determine exposure to ionizing radiation (IR) that can also be easily scaled to multiple testing sites in emergency situations...
High-throughput biodosimetry methods to determine exposure to ionizing radiation (IR) that can also be easily scaled to multiple testing sites in emergency situations are needed in the event of malicious attacks or nuclear accidents that may involve a substantial number of civilians. In the event of an improvised nuclear device (IND), a complex IR exposure will have a very high-dose rate (VHDR) component from an initial blast. We have previously addressed low-dose rate (LDR, ≤1 Gy/day) exposures from internal emitters on biofluid small molecule signatures, but further research on the VHDR component of the initial blast is required. Here, we exposed 8- to 10-week-old male C57BL/6 mice to an acute dose of 3 Gy using a reference dose rate of 0.7 Gy/min or a VHDR of 7 Gy/s, collected urine and serum at 1 and 7 d, then compared the metabolite signatures using either untargeted (urine) or targeted (serum) approaches with liquid chromatography mass spectrometry platforms. A Random Forest classification approach showed strikingly similar changes in urinary signatures at 1 d post-irradiation with VHDR samples grouping closer to control samples at 7 d. Identical metabolite panels (carnitine, trigonelline, xanthurenic acid, N6,N6,N6-trimethyllysine, spermine, and hexosamine-valine-isoleucine-OH) could differentiate IR exposed individuals with high sensitivity and specificity (area under the receiver operating characteristic (AUROC) curves 0.89-1.00) irrespective of dose rate at both days. For serum, the top 25 significant lipids affected by IR exposure showed slightly higher perturbations at 0.7 Gy/min vs. 7 Gy/s; however, identical panels showed excellent sensitivity and specificity at 1 d (three hexosylceramides (16:0), (18:0), (24:0), sphingomyelin [26:1], lysophosphatidylethanolamine [22:1]). Mice could not be differentiated from control samples at 7 d for a 3 Gy exposure based on serum lipid signatures. As with LDR exposures, we found that identical biofluid small molecule signatures can identify IR exposed individuals irrespective of dose rate, which shows promise for more universal applications of metabolomics for biodosimetry.
PubMed: 35736453
DOI: 10.3390/metabo12060520 -
BMC Pregnancy and Childbirth May 2023Neuraxial labor analgesia has been associated with fetal heart rate changes. Fetal bradycardia is multifactorial, and predicting it poses a significant challenge to...
BACKGROUND
Neuraxial labor analgesia has been associated with fetal heart rate changes. Fetal bradycardia is multifactorial, and predicting it poses a significant challenge to clinicians. Machine learning algorithms may assist the clinician to predict fetal bradycardia and identify predictors associated with its presentation.
METHODS
A retrospective analysis of 1077 healthy laboring parturients receiving neuraxial analgesia was conducted. We compared a principal components regression model with tree-based random forest, ridge regression, multiple regression, a general additive model, and elastic net in terms of prediction accuracy and interpretability for inference purposes.
RESULTS
Multiple regression identified combined spinal-epidural (CSE) (p = 0.02), interaction between CSE and dose of phenylephrine (p < 0.0001), decelerations (p < 0.001), and the total dose of bupivacaine (p = 0.03) as associated with decrease in fetal heart rate. Random forest exhibited good predictive accuracy (mean standard error of 0.92).
CONCLUSION
Use of CSE, presence of decelerations, total dose of bupivacaine, and total dose of vasopressors after CSE are associated with decreases in fetal heart rate in healthy parturients during labor. Prediction of changes in fetal heart rate can be approached with a tree-based random forest model with good accuracy with important variables that are key for the prediction, such as CSE, BMI, duration of stage 1 of labor, and dose of bupivacaine.
Topics: Pregnancy; Female; Humans; Heart Rate, Fetal; Bradycardia; Retrospective Studies; Analgesia, Epidural; Analgesia, Obstetrical; Bupivacaine
PubMed: 37211590
DOI: 10.1186/s12884-023-05632-3 -
Radiation Research Nov 2020Internal contamination by radionuclides may constitute a major source of exposure and biological damage after radiation accidents and potentially in a dirty bomb or...
Internal contamination by radionuclides may constitute a major source of exposure and biological damage after radiation accidents and potentially in a dirty bomb or improvised nuclear device scenario. We injected male C57BL/6 mice with radiolabeled cesium chloride solution (137CsCl) to evaluate the biological effects of varying cumulative doses and dose rates in a two-week study. Injection activities of 137CsCl were 5.71, 6.78, 7.67 and 9.29 MBq, calculated to achieve a target dose of 4 Gy at days 14, 7, 5 and 3, respectively. We collected whole blood samples at days 2, 3, 5, 7 and 14 so that we can publish the issue in Decemberfrom all injection groups and measured gene expression using Agilent Mouse Whole Genome microarrays. We identified both dose-rate-independent and dose-rate-dependent gene expression responses in the time series. Gene Ontology analysis indicated a rapid and persistent immune response to the chronic low-dose-rate irradiation, consistent with depletion of radiosensitive B cells. Pathways impacting platelet aggregation and TP53 signaling appeared activated, but not consistently at all times in the study. Clustering of genes by pattern and identification of dose-rate-independent and -dependent genes provided insight into possible drivers of the dynamic transcriptome response in vivo, and also indicated that TP53 signaling may be upstream of very different transcript response patterns. This characterization of the biological response of blood cells to internal radiation at varying doses and dose rates is an important step in understanding the effects of internal contamination after a nuclear event.
Topics: Animals; Cesium Radioisotopes; DNA Repair; Gene Ontology; Male; Mice; Radiation Dosage
PubMed: 32931585
DOI: 10.1667/RADE-20-00041 -
Journal of Radiation Research Mar 2022Intestinal organoids are an in vitro cultured tissue model generated from intestinal stem cells, and they contain a mixture of epithelial cell types. We previously...
Intestinal organoids are an in vitro cultured tissue model generated from intestinal stem cells, and they contain a mixture of epithelial cell types. We previously established an efficient 'one cell/well' sorting method, and defined organoid-forming potential (OFP) as a useful index to evaluate the stemness of individual cells. In this study, we assessed the response to radiation dose and dose-rate by measuring both OFP and the percentage of stem cells in the crypts. After high-dose-rate (HDR, 0.5 Gy/min) irradiation in vivo, the percentage of stem cells in the harvested crypt cells decreased, and the replenishment of cycling stem cells originating from dormant cells was enhanced, but OFP increased in cells irradiated with a total dose of >1 Gy. In contrast, at a total dose of 0.1 Gy the percentage of stem cells reduced slightly, but neither replenishment rate nor OFP changed. Furthermore, the response to 1 Gy of low-dose-rate (LDR) irradiation was similar to the response to 0.1 Gy HDR irradiation. These results suggest that 0.1 Gy HDR irradiation or 1 Gy LDR irradiation does not alter stemness. Additionally, the OFP increase in the colon in response to irradiation was smaller than that in the duodenum, similar to the percentage of stem cells. Understanding the differences in the response of stem cells between the colon and the duodenum to radiation is important to clarify the mechanisms underlying the development of radiation-associated intestinal cancers.
Topics: Dose-Response Relationship, Radiation; Intestines; Organoids; Radiation Dosage; Radiation, Ionizing; Stem Cells
PubMed: 34977948
DOI: 10.1093/jrr/rrab120 -
Cancers Dec 2020Prostate cancer (PCa) is the most common noncutaneous solid organ malignancy among men worldwide. Radiation therapy is a standard of care treatment option that has... (Review)
Review
Prostate cancer (PCa) is the most common noncutaneous solid organ malignancy among men worldwide. Radiation therapy is a standard of care treatment option that has historically been delivered in the form of small daily doses of radiation over the span of multiple weeks. PCa appears to have a unique sensitivity to higher doses of radiation per fraction, rendering it susceptible to abbreviated forms of treatment. Stereotactic body radiation therapy (SBRT) and high-dose-rate brachytherapy (HDRBT) are both modern radiation modalities that allow the precise delivery of ablative doses of radiation to the prostate while maximally sparing sensitive surrounding normal structures. In this review, we highlight the evidence regarding the radiobiology, oncological outcomes, toxicity and dose/fractionation schemes of SBRT and HDRBT monotherapy in men with low-and intermediate-risk PCa.
PubMed: 33276562
DOI: 10.3390/cancers12123606 -
Journal of Contemporary Brachytherapy Dec 2020Brachytherapy-based radiotherapy has been applied for decades in the curative treatment for solitary, ≤ 5 cm bladder tumors. This review provides a historical... (Review)
Review
Brachytherapy-based radiotherapy has been applied for decades in the curative treatment for solitary, ≤ 5 cm bladder tumors. This review provides a historical perspective of this organ sparing approach. A systematic search of the published literature between 1900 and 2019 was performed on the subject of bladder brachytherapy using PubMed, with digitally retrievable articles being supplemented with articles from the personal collection of the authors. The articles were divided into consecutive time periods, each reflecting the impact of authors on the development of brachytherapy treatment: the time of pioneers, early innovators, modifiers, and recent innovators. Three case-controlled studies comparing brachytherapy-based organ-sparing treatment with cystectomy, demonstrated similarity between the two approaches in terms of disease-free and overall survival, whereas brachytherapy-based approach offered the advantage of at least 80% chance of bladder preservation. The overview was organized in a chronological order, starting from the evolution of brachytherapy from radium, followed by remote afterloading and dose-rate adjustments, and closing with modern era of high-dose-rate and image-guided brachytherapy. Importantly, we demonstrated how essential and beneficial for the patients is a close collaboration between radiation oncologists and urologists, and how adopting a modern surgical development, i.e. the laparoscopic implantation technique, which later became robot-assisted, contributed to the success of this multidisciplinary brachytherapy treatment. We concluded that this highly effective brachytherapy method with very limited toxicity deserves more worldwide popularity.
PubMed: 33437312
DOI: 10.5114/jcb.2020.101697 -
Journal of Radiation Research Mar 2023While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal... (Review)
Review
While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal models have made significant contributions to provide quantitative data with mechanistic insights. The current article aims at compiling the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. This review focuses specifically on the results that explain the biological mechanisms underlying dose-rate effects and their potential involvement in radiation-induced carcinogenic processes. Since the adverse outcome pathway (AOP) concept together with the key events holds promise for improving the estimation of radiation risk at low doses and low dose-rates, the review intends to scrutinize dose-rate dependency of the key events in animal models and to consider novel key events involved in the dose-rate effects, which enables identification of important underlying mechanisms for linking animal experimental and human epidemiological studies in a unified manner.
Topics: Animals; Humans; Radiation Dosage; Neoplasms, Radiation-Induced; Risk Assessment; Radiation Exposure; Models, Animal; Liver; Lung; Hematopoietic System; Dose-Response Relationship, Radiation
PubMed: 36773331
DOI: 10.1093/jrr/rrad003 -
Journal of Radiation Research Sep 2021A microSilicon™ (PTW type 60023), a new unshielded diode detector succeeding Diode E (model 60017, PTW), was characterized for electron beam dosimetry and compared...
A microSilicon™ (PTW type 60023), a new unshielded diode detector succeeding Diode E (model 60017, PTW), was characterized for electron beam dosimetry and compared with other detectors. Electron beams generated from a TrueBeam linear accelerator were measured using the microSilicon, Diode E, and microDiamond synthetic single-crystal diamond detector. Positional accuracy of microSilicon was measured by data collected in air and water. The percent depth dose (PDD), off-center ratio (OCR), dose-response linearity, dose rate dependence, and cone factors were evaluated. The PDDs were compared with data measured using a PPC40 plane-parallel ionization chamber. The maximum variations of depth of 50% and 90% of the maximum dose, and practical depth among all detectors and energies were 0.9 mm. The maximum variations of the bremsstrahlung dose among all detectors and energies were within 0.3%. OCR showed good agreement within 1% for the flat and tail regions. The microSilicon detector showed a penumbra width similar to microDiamond, whereas Diode E showed the steepest penumbra shape. All detectors showed good dose-response linearity and stability against the dose rate; only Diode E demonstrated logarithmic dose rate dependency. The cone factor measured with microSilicon was within ±1% for all energies and cone sizes. We demonstrated that the characteristics of microSilicon is suitable for electron beam dosimetry. The microSilicon detector can be a good alternative for electron beam dosimetry in terms of providing an appropriate PDD curve without corrections, high spatial resolution for OCR measurements and cone factors.
PubMed: 34559877
DOI: 10.1093/jrr/rrab085 -
Emerging Infectious Diseases Jul 2022Despite extensive technological advances in recent years, objective and continuous assessment of physiologic measures after vaccination is rarely performed. We conducted... (Observational Study)
Observational Study
Despite extensive technological advances in recent years, objective and continuous assessment of physiologic measures after vaccination is rarely performed. We conducted a prospective observational study to evaluate short-term self-reported and physiologic reactions to the booster BNT162b2 mRNA (Pfizer-BioNTech, https://www.pfizer.com) vaccine dose. A total of 1,609 participants were equipped with smartwatches and completed daily questionnaires through a dedicated mobile application. The extent of systemic reactions reported after the booster dose was similar to that of the second dose and considerably greater than that of the first dose. Analyses of objective heart rate and heart rate variability measures recorded by smartwatches further supported this finding. Subjective and objective reactions after the booster dose were more apparent in younger participants and in participants who did not have underlying medical conditions. Our findings further support the safety of the booster dose from subjective and objective perspectives and underscore the need for integrating wearables in clinical trials.
Topics: BNT162 Vaccine; COVID-19; Humans; RNA, Messenger; Self Report; Vaccination
PubMed: 35654410
DOI: 10.3201/eid2807.212330 -
Neurosurgery Dec 2019Gamma Knife radiosurgery (GKRS; Elekta AB) remains a well-established treatment modality for vestibular schwannomas. Despite highly effective tumor control, further...
BACKGROUND
Gamma Knife radiosurgery (GKRS; Elekta AB) remains a well-established treatment modality for vestibular schwannomas. Despite highly effective tumor control, further research is needed toward optimizing long-term functional outcomes. Whereas dose-rate effects may impact post-treatment toxicities given tissue dose-response relationships, potential effects remain largely unexplored.
OBJECTIVE
To evaluate treatment outcomes and potential dose-rate effects following definitive GKRS for vestibular schwannomas.
METHODS
We retrospectively reviewed 419 patients treated at our institution between 1998 and 2015, characterizing baseline demographics, pretreatment symptoms, and GKRS parameters. The cohort was divided into 2 dose-rate groups based on the median value (2.675 Gy/min). Outcomes included clinical tumor control, radiographic progression-free survival, serviceable hearing preservation, hearing loss, and facial nerve dysfunction (FND). Prognostic factors were assessed using Cox regression.
RESULTS
The study cohort included 227 patients with available follow-up. Following GKRS 2-yr and 4-yr clinical tumor control rates were 98% (95% CI: 95.6%-100%) and 96% (95% CI: 91.4%-99.6%), respectively. Among 177 patients with available radiographic follow-up, 2-yr and 4-yr radiographic progression-free survival rates were 97% (95% CI: 94.0%-100.0%) and 88% (95% CI: 81.2%-95.0%). The serviceable hearing preservation rate was 72.2% among patients with baseline Gardner-Robertson class I/II hearing and post-treatment audiological evaluations. Most patients experienced effective relief from prior headaches (94.7%), tinnitus (83.7%), balance issues (62.7%), FND (90.0%), and trigeminal nerve dysfunction (79.2%), but not hearing loss (1.0%). Whereas GKRS provided effective tumor control independently of dose rate, GKRS patients exposed to lower dose rates experienced significantly better freedom from post-treatment hearing loss and FND (P = .044).
CONCLUSION
Whereas GKRS provides excellent tumor control and effective symptomatic relief for vestibular schwannomas, dose-rate effects may impact post-treatment functional outcomes. Further research remains warranted.
Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Female; Follow-Up Studies; Hearing; Hearing Loss; Hearing Tests; Humans; Male; Middle Aged; Neuroma, Acoustic; Radiation Dosage; Radiosurgery; Retrospective Studies; Treatment Outcome
PubMed: 31270543
DOI: 10.1093/neuros/nyz229