Near-Infrared II Photobiomodulation Preconditioning Ameliorates Stroke Injury via Phosphorylation of eNOS.

BACKGROUND: The current management of patients with stroke with intravenous thrombolysis and endovascular thrombectomy is effective only when it is timely performed on an appropriately selected but minor fraction of patients. The development of novel adjunctive therapy is highly desired to reduce morbidity and mortality with stroke. Since endothelial dysfunction is implicated in the pathogenesis of stroke and is featured with suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency, restoring endothelial nitric oxide represents a promising approach to treating stroke injury. METHODS: This is a preclinical proof-of-concept study to determine the therapeutic effect of transcranial treatment with a low-power near-infrared laser in a mouse model of ischemic stroke. The laser treatment was performed before the middle cerebral artery occlusion with a filament. To determine the involvement of eNOS phosphorylation, unphosphorylatable eNOS S1176A knock-in mice were used. Each measurement was analyzed by a 2-way ANOVA to assess the effect of the treatment on cerebral blood flow with laser Doppler flowmetry, eNOS phosphorylation by immunoblot analysis, and stroke outcomes by infarct volumes and neurological deficits. RESULTS: Pretreatment with a 1064-nm laser at an irradiance of 50 mW/cm2 improved cerebral blood flow, eNOS phosphorylation, and stroke outcomes. CONCLUSIONS: Near-infrared II photobiomodulation could offer a noninvasive and low-risk adjunctive therapy for stroke injury. This new modality using a physical parameter merits further consideration to develop innovative therapies to prevent and treat a wide array of cardiovascular diseases.

Natural radionuclides and radiological risk assessment in the stream and river sediments of a high background natural radiation area Kanyakumari, India.

The Kanyakumari coast is known to be a high background natural radiation area due to the placer deposits of heavy minerals such as ilmenite, monazite, and rutile. The Kanyakumari river sediments that could be the source of the elevated amounts of natural radionuclides in the coastal sands have been studied in this paper. The activity concentrations of primordial radionuclides 226Ra, 232Th, and 40K were determined using high-purity germanium (HPGe) gamma-ray spectrometry. The mean activity concentrations of 226Ra, 232Th, and 40K were found to be 75 Bq kg-1, 565 Bq kg-1, and 360 Bq kg-1, respectively. The mean absorbed dose rate was 395 nGy h-1. Radiological hazard parameters were studied and compared with the world average values. The contribution of 232Th to the total dose rate was found to be higher than that of the two other radionuclides. The high mean ratio of 232Th/226Ra suggested an enrichment of 232Th and the occurrence of 226Ra leaching due to an oxidizing environment. Principal component analysis (PCA) was carried out for the radionuclides in order to discriminate the source of the sediments. This study provides new insights into the distribution of natural radionuclides in sediments of rivers and streams.

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1-heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary-specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR-Cas9-based genome editing. Homozygotes (Brca1L63X/L63X ) were embryonic lethal, whereas heterozygotes (Brca1L63X/+ ) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild-type (WT) littermates during their lifetime. Intraperitoneal injection of 1-methyl-1-nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1-2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose-dependent mammary carcinogenesis with 0.8 Gy-1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1L63X/+ rats thus offer the first single-mutation, heterozygous model of BRCA1-associated breast cancer, especially with exposure to a DNA break-inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high-risk BRCA1 mutations.

Fast and Durable Intraoperative Near-infrared Imaging of Ovarian Cancer Using Ultrabright Squaraine Fluorophores.

The residual tumor after surgery is the most significant prognostic factor of patients with epithelial ovarian cancer. Near-infrared (NIR) fluorescence-guided surgery is actively utilized for tumor localization and complete resection during surgery. However, currently available contrast-enhancing agents display low on-target binding, unfavorable pharmacokinetics, and toxicity, thus not ideal for clinical use. Here we report ultrabright and stable squaraine fluorophores with optimal pharmacokinetics by introducing an asymmetric molecular conformation and surface charges for rapid transporter-mediated cellular uptake. Among the tested, OCTL14 shows low serum binding and rapid distribution into cancer tissue via organic cation transporters (OCTs). Additionally, the charged squaraine fluorophores are retained in lysosomes, providing durable intraoperative imaging in a preclinical murine model of ovarian cancer up to 24 h post-injection. OCTL14 represents a significant departure from the current bioconjugation approach of using a non-targeted fluorophore and would provide surgeons with an indispensable tool to achieve optimal resection.

ICP-MS Measurement of Trace and Rare Earth Elements in Beach Placer-Deposit Soils of Odisha, East Coast of India, to Estimate Natural Enhancement of Elements in the Environment.

Inductively coupled plasma mass spectrometry (ICP-MS) has been used to measure the concentration of trace and rare earth elements (REEs) in soils. Geochemical certified reference materials such as JLk-1, JB-1, and JB-3 were used for the validation of the analytical method. The measured values were in good agreement with the certified values for all the elements and were within 10% analytical error. Beach placer deposits of soils mainly from Odisha, on the east coast of India, have been selected to study selected trace and rare earth elements (REEs), to estimate enrichment factor (EF) and geoaccumulation index (Igeo) in the natural environment. Enrichment factor (EF) and geoaccumulation index (Igeo) results showed that Cr, Mn, Fe, Co, Zn, Y, Zr, Cd and U were significantly enriched, and Th was extremely enriched. The total content of REEs (Æ©REEs) ranged from 101.3 to 12,911.3 µg g-1, with an average 2431.1 µg g-1 which was higher than the average crustal value of ΣREEs. A high concentration of Th and light REEs were strongly correlated, which confirmed soil enrichment with monazite minerals. High ratios of light REEs (LREEs)/heavy REEs (HREEs) with a strong negative Eu anomaly revealed a felsic origin. The comparison of the chondrite normalized REE patterns of soil with hinterland rocks such as granite, charnockite, khondalite and migmatite suggested that enhancement of trace and REEs are of natural origin.

Chemical Separation of Uranium and Precise Measurement of 234U/238U and 235U/238U Ratios in Soil Samples Using Multi Collector Inductively Coupled Plasma Mass Spectrometry.

A new chemical separation has been developed to isolate uranium (U) using two UTEVA columns to minimize iron and thorium interferences from high background area soil samples containing minerals like monazites and ilmenite. The separation method was successfully verified in some certified reference materials (CRMs), for example, JSd-2, JLk-1, JB-1 and JB-3. The same method was applied for purification of U in Fukushima soil samples affected by the Fukushima dai-ichi nuclear power station (FDNPS) accident. Precise and accurate measurement of 234U/238U and 235U/238U isotope ratios in chemically separated U were carried out using a multi-collector inductively coupled plasma mass spectrometer (MC-ICP-MS). In this mass spectrometric method, an array of two Faraday cups (1011 Ω, 1012 Ω resistor) and a Daly detector were simultaneously employed. The precision of U isotope ratios in an in-house standard was evaluated by replicate measurement. Relative standard deviation (RSD) of 234U/238U and 235U/238U were found to be 0.094% (2σ) and 0.590% (2σ), respectively. This method has been validated using a standard reference material SRM 4350B, sediment sample. The replicate measurements of 234U/238U in SRM shows 0.7% (RSD). This developed method is suitable for separation of U and its isotope ratio measurement in environmental samples.

Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium.

RATIONALE: Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear. OBJECTIVE: To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model. METHODS AND RESULTS: Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups. CONCLUSIONS: This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.

Energy resolution improvement in simplified alpha spectroscopy for radionuclidic purity tests on 225Ac production floors.

This study investigated the feasibility of a simplified method of alpha spectroscopy for radionuclidic purity tests at 225Ac production sites that eliminates the need for a vacuum chamber. The impact of enhancing the energy resolution using a collimator was evaluated through radiation transport simulations. The results showed that a full width at tenth maximum (FWTM) of <300 keV was achieved for alpha particles from 241Am, for which the main energy peak was 5.5 MeV. Experimental validation using an electrodeposition source containing 237Np, 241Am, and 244Cm confirmed an FWTM of 272 keV for both 241Am and 244Cm. These two peaks, with a difference of ~300 keV, were effectively separated. In response to the growing demand for targeted radioisotope therapy, this simplified alpha spectroscopy method offers the potential to detect 226Ra mixed with 225Ac generated by accelerators, given the alpha energy difference of ~700 keV.

Distribution of naturally occurring radionuclides and gamma dose rate assessment in the soils of high background natural radiation area Odisha, India.

A study on the activity concentration of primordial radionuclides 226Ra, 232Th and 40K was carried out on the surface soil samples collected from the coastal villages between Chhatrapur and Gopalpur regions of high background natural radiation area Odisha, India, using high purity germanium gamma spectroscopy. The mean activity concentrations of 226Ra, 232Th and 40K were found to be 231, 1692 and 250 Bq/kg, respectively. The total mean absorbed dose owing to the presence of 226Ra, 232Th and 40K was 1139 nGy/h. The mean annual effective dose was found to be 1397 µSv/y and higher than the UNSCEAR average value 70 µSv/y.

234U/238U disequilibrium and 235U/238U ratios measured using MC-ICP-MS in natural high background radiation area soils to understand the fate of uranium.

The Chhatrapur-Gopalpur coastal area in Odisha, India is a well-known natural high background radiation (HBRA) area due to the abundance of monazite (a thorium bearing radioactive mineral) in beach sands and soils. Recent studies on Chhatrapur-Gopalpur HBRA groundwater have reported high concentrations of uranium and its decay products. Therefore, the soils of the Chhatrapur-Gopalpur HBRA are reasonably suspected as the sources of these high uranium concentrations in groundwater. In this report, first the uranium concentrations in soil samples were measured using inductively coupled plasma mass spectrometry (ICP-MS) and they were found to range from 0.61 ± 0.01 to 38.59 ± 0.16 mg kg-１. Next, the 234U/238U and 235U/238U isotope ratios were measured to establish a baseline for the first time in Chhatrapur-Gopalpur HBRA soil. Multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) was used for measurement of these isotope ratios. The 235U/238U ratio was observed to be the normal terrestrial value. The 234U/238U activity ratio, was calculated to understand the secular equilibrium between 234U and 238U in soil and it varied from 0.959 to 1.070. To understand the dynamics of uranium in HBRA soil, physico-chemical characteristics of soil were correlated with uranium isotope ratios and this correlation of 234U/238U activity ratio indicated the leaching of 234U from Odisha HBRA soil.

[Development of a simple quantitative method for the strontium-89 concentration of radioactive liquid waste using the plastic scintillation survey meter for beta rays].

Strontium-89 (89Sr: pure beta, E; 1.495 MeV-100%, halflife: 50.5 days) chloride is used as pain relief from bone metastases. An assay of 89Sr is difficult because of a pure beta emitter. For management of 89Sr, we tried to evaluate a simple quantitative method for the 59Sr concentration of radioactive liquid waste using scintillation survey meter for beta rays. The counting efficiency of the survey meter with this method was 35.95%. A simple 30 minutes measurement of 2 ml of the sample made the quantitative measurement of 89Sr practical. Reducing self-absorption of the beta ray in the solution by counting on the polyethlene paper improved the counting efficiency. Our method made it easy to manage the radioactive liquid waste under the legal restrictions.

[Different educational programs on medical ultrasound examination for radiological technologists and medical technologists].

Radiological technologists (RTs) and medical technologists (MTs) are legally allowed to work as sonographers performing medical ultrasound examination. Despite the total number, much fewer RTs work as sonographers than MTs. To explore the reason, we investigated educational programs, universities, and colleges for both specialties. First, we established five categories of sonographers' competency: 1) Anatomy for imaging diagnosis, 2) Diseases and diagnosis, 3) Imaging, 4) Structure and principle of the equipment, and 5) Evaluation of image quality, using competence reported by the International Society of Radiographers and Radiological Technologists (ISRRT) and diagnostic competency required of sonographers in Japan. Using these categories, we analyzed the content and total instruction time by lectures and seminars based on information written in the syllabi, and explored the differences in education related to sonographers' competency in both programs. "Anatomy for imaging diagnosis" was taught in 15 RT programs (93.8%), and 6 MT programs (31.6%). "Diseases and diagnosis" was taught in 13 RT programs (86.7%), and 8 MT programs (53.3%). "Imaging" was taught in 14 RT programs (100%), and 13 MT programs (76.5%). "Structure and principle of the equipment" was taught in 12 RT programs (85.7%), and 6 MT programs (31.6%). "Evaluation of image quality" was taught in 11 RT programs (84.6%), and 3 MT programs (15.0%). The average instruction time for RT was longer than for MT programs in all categories. RTs are educated and have a foundation to be sonographers at graduation, and may have the possibility to expand their career in this field.

[PET Research in Clinical Oncology].

Positron emission tomography (PET) in nuclear medicine is especially used for diagnosis in clinical oncology, and PET/CT examination using 18F-FDG is very useful for staging and therapy evaluation of cancer. The excellent property of PET diagnosis is that the functional information of cells can be evaluated quantitatively, but it also has the problem that its quantitative value fluctuates depending on image reconstruction conditions and body movements/respiratory movements. In this paper, we summarize the PET research that has been conducted so far in clinical oncology, and also introduce our researches for improve the quantitativeness.

[Study on the Concentration of Radioactive Cesium in the Environment after the Fukushima Daiichi Nuclear Power Plant Accident].

The Tohoku-Pacific Ocean Earthquake that occurred on March 11, 2011 and the resulting tsunami caused the loss of many people and extensive damage in a wide area. Among the anthropogenic radionuclides dispersed from the Fukushima Daiichi Nuclear Power Plant, 134Cs and 137Cs have very long half-lives of approximately 2 years and 30 years, respectively, and there are concerns about their uptake into soil and living things. This paper describes a study conducted by the authors' group on radiocesium activity concentrations in the environment.

DISTRIBUTION OF GAMMA RADIATION DOSE RATE AND ACTIVITY CONCENTRATION IN SOIL RELATED WITH NATURAL RADIONUCLIDES ON TAIWAN MAIN ISLAND.

To enable precise assessment of health impacts following a nuclear power plant accident, extensive and detailed data on environmental radiation levels are needed. This study was undertaken to investigate the air and the soil radiation levels using a car-borne survey on the main island of Taiwan where no extensive environmental radiation distribution survey had been conducted before. The mean air absorbed dose rate on this island was 57 ± 10 nGy h-1. The measured dose rate distribution varied depending on the geology of the soils, and ranged from 22 to 113 nGy h-1. The mean radiation level in soil was 539 ± 124 Bq kg-1 for 40K, 23 ± 8 Bq kg-1 for 238U and 41 ± 22 Bq kg-1 for 232Th. The air absorbed dose rate (58 nGy h-1) calculated from these data of mean radiation level in soil was comparable to that determined by the car-borne survey method. Thus, this study yielded detailed data on air absorbed dose rate depending primarily on the geology of the soils on the main island of Taiwan.

DISTRIBUTION OF RADIOCESIUM CONCENTRATIONS OF SOILS IN THE EIGHT IZU ISLANDS AFTER THE FUKUSHIMA DAIICHI NUCLEAR POWER PLANT ACCIDENT.

Large amounts of anthropogenic radionuclides, such as 134Cs and 137Cs(radiocesium), were released into the atmosphere due to the Fukushima Daiichi Nuclear Power Plant (F1-NPP) accident and were transported into various environments. The soil accumulations of diffused radionuclides are marked by large differences in their horizontal distributions, and the vertical air dose rates vary depending on the topography, altitude and other factors. In this study, soil activity concentrations of eight islands in the Izu Islands, ~334-563 km south of the F1-NPP, were analyzed from both horizontal and vertical perspectives. Soil samples were collected over a 4-y period from 2012 to 2016, and their activity concentrations of radiocesium were measured. The activity concentrations in the soil were categorized for intervals of a 100-m altitude above sea level, and the relationship between the maximum activity concentration in each category and the distance from the F1-NPP was analyzed. The correlation was good at the lower altitudes.

[Questionnaire Survey of Japanese Medical Physicists on Working Conditions in 2020].

The questionnaire survey was conducted in 2020 to investigate the working conditions of qualified medical physicists in Japan. We developed a web-based system for administering the questionnaire and surveyed 1,228 qualified medical physicists. The number of received responses was 405. We summarized the results of the survey by job category. The obtained results showed that most of the people working as certified medical physicists met the following conditions: (1) position of healthcare occupation, (2) direct supervisor is a medical doctor or a medical physicist, (3) licensed or passed an examination for a Class I Radiation Protection Supervisor, (4) without the license of professional radiotherapy technologist, (5) master's or doctor's degree, (6) being assigned to the section that is different from the radiological technologist section. The average annual salary was approximately 600,000 yen higher for those employed as medical physicists than for those employed as radiotherapy technologists. The percentage of work performed by a certified medical physicist in radiation therapy greatly varies depending on whether the physicist is dedicated to treatment planning and equipment quality control. Alternatively, the proportion of the true duties of medical physicists in charge of radiation therapy, as considered by qualified medical physicists in radiation therapy, was the same regardless of whether they were working full-time or not. The results of this survey updated the working status of certified medical physicists in Japan. We will continue to conduct the survey periodically and update the information to contribute to the improvement of the working conditions of medical physicists and policy recommendations.

Environmental Enrichment Increases Radiation-induced Apoptosis Not Spontaneous Apoptosis in Mouse Intestinal Crypt Cells.

BACKGROUND/AIM: An enriched environment (EE) modifies apoptotic cell death and promotes cell proliferation in the central nervous system (CNS) in mice. However, few studies have examined the effects of an EE on apoptosis in non-CNS organs in model orgamisms. In addition, the intestinal tract is one of organs at high-risk of carcinogenesis after radiation exposure. Herein we evaluated the effects of an EE on spontaneous and radiation-induced apoptosis in intestinal crypt cells of mice. MATERIALS AND METHODS: Juvenile (3-week-old) and adult (11-week-old) male B6C3F1 mice were housed in a standard environment or EE for 8 weeks and then were whole-body irradiated with 2 Gy X-rays. Apoptosis in the small intestine and colon was analyzed with antibody against cleaved caspase 3. RESULTS: The EE significantly reduced body weight; adipose tissue weight; and serum levels of total cholesterol, triglyceride, leptin, and insulin. Although EE did not change the spontaneous apoptotic index without irradiation, it significantly increased the index after irradiation in the colonic crypt. The apoptotic index in the small intestinal crypt showed similar patterns. CONCLUSION: An EE enhances radiation-induced apoptosis of stem/progenitor cells in the small intestine and colon without affecting spontaneous apoptosis. An EE may thus reduce the risk of cancer in the intestinal tract after radiation exposure such as radiotherapy.

Measurements and future projections of Gd-based contrast agents for MRI exams in wastewater treatment plants in the Tokyo metropolitan area.

Large amounts of Gd-based contrast agents are used in magnetic resonance imaging (MRI) that are then excreted in urine. These agents are subsequently discharged into the environment because they are difficult to remove by usual sewage treatment techniques. In this study, changes of the Gd anomaly during wastewater treatment processes were determined by analyzing wastewater samples and the possibility for future prediction of the changes was evaluated based on the relationship between the Gd anomaly and the number of MRI devices in use. After the wastewater treatment processes, the values of final effluent were increased 1.8 times compared to those of influent, and the Gd anomaly of effluent had a positive correlation to the number of MRI devices. The finding suggested that the changes of environmental impact were predictable based on the number of MRI devices.

Topical pH Sensing NIR Fluorophores for Intraoperative Imaging and Surgery of Disseminated Ovarian Cancer.

Fluorescence-guided surgery (FGS) aids surgeons with real-time visualization of small cancer foci and borders, which improves surgical and prognostic efficacy of cancer. Despite the steady advances in imaging devices, there is a scarcity of fluorophores available to achieve optimal FGS. Here, 1) a pH-sensitive near-infrared fluorophore that exhibits rapid signal changes in acidic tumor microenvironments (TME) caused by the attenuation of intramolecular quenching, 2) the inherent targeting for cancer based on chemical structure (structure inherent targeting, SIT), and 3) mitochondrial and lysosomal retention are reported. After topical application of PH08 on peritoneal tumor regions in ovarian cancer-bearing mice, a rapid fluorescence increase (< 10 min), and extended preservation of signals (> 4 h post-topical application) are observed, which together allow for the visualization of submillimeter tumors with a high tumor-to-background ratio (TBR > 5.0). In addition, PH08 is preferentially transported to cancer cells via organic anion transporter peptides (OATPs) and colocalizes in the mitochondria and lysosomes due to the positive charges, enabling a long retention time during FGS. PH08 not only has a significant impact on surgical and diagnostic applications but also provides an effective and scalable strategy to design therapeutic agents for a wide array of cancers.