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.

A new simpler image quality index based on body size for FDG-PET/CT.

Noise equivalent count density (NEC density ) is often used to evaluate the image quality of whole-body fluorodeoxyglucose tomography tests. However, this index is calculated using the patient volume, which is difficult to obtain at every facility. In this study, we proposed new image quality indices that can be evaluated at all facilities. In total, 94 patients were enrolled in the study. The correlations of patients' body weight and BMI with volume were examined. New image quality indices normalized by body weight and BMI were defined as NEC bw and NEC bmi , respectively. Correlations between NEC bw , NEC bmi , and NEC density were examined. Further, the correlations between these two new indices and visual scores were evaluated. Good correlations were observed between volume and body weight (r = 0.861, P  < 0.001) and between volume and BMI (r = 0.728, P  < 0.001). NEC bw and NEC bmi correlated well with NEC density (r = 0.954 for NEC bw and r = 0.897 for NEC bmi , P  < 0.001). These correlations improved when the examined bed positions were set to the same number. Additionally, the correlations of visual scores with NEC bw and NEC bmi were similar to those between the visual score and NEC density . Our investigation indicated that the newly proposed image quality metrics, NEC bw and NEC bmi , were easily calculated and as useful as NEC density for evaluating image quality when subjects had similar physiques.

Comparing Efficacy Between Robust and PTV Margin-based Optimizations for Interfractional Anatomical Variations in Prostate Tomotherapy.

BACKGROUND/AIM: Interfractional anatomical variations cause considerable differences between planned and actual radiotherapy doses. This study aimed to investigate the efficacy of robust and planning target volume (PTV) margin-based optimizations for the anatomical variations in helical tomotherapy for prostate cancer. PATIENTS AND METHODS: Ten patients underwent treatment-planning kilovolt computed tomography (kVCT) and daily megavolt computed tomography (MVCT). Two types of nominal plans, with a prescription of 60 Gy/20 fractions, were created using robust and PTV margin-based optimizations on kVCT for each patient. Subsequently, the daily estimated doses were recalculated using nominal plans, and all available MVCTs modified the daily patient-setup errors. Due to the difference in dose calculation accuracy between kVCT and MVCT, three scenarios with dose corrections of 1, 2, and 3% were considered in the recalculation process. The dosimetric metrics, including target coverage with the prescription dose, Paddick's conformity index, homogeneity index, and mean dose to the rectum, were analyzed. RESULTS: A dosimetric comparison of the nominal plans demonstrated that the robust plans had better dose conformity, lower target coverage, and dose homogeneity than the PTV plans. In the daily estimated doses of any dose-corrected scenario, the target coverage and dose sparing to the rectum in the robust plans were significantly higher than those in the PTV plans, whereas dose conformity and homogeneity were identical to those of the nominal case. CONCLUSION: Robust optimization is recommended as it accounts for anatomical variations during treatment regarding target coverage in helical tomotherapy plans for prostate cancer.

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.

Impact of delivery time factor on treatment time and plan quality in tomotherapy.

Delivery time factor (DTF) is a new parameter introduced by the RayStation treatment planning system for tomotherapy treatment planning. This study investigated the effects of this factor on various tomotherapy plans. Twenty-five patients with cancer (head and neck, 6; lung, 9; prostate, 10) were enrolled in this study. Helical tomotherapy plans with a field width of 2.5 cm, pitch of 0.287, and DTF of 2.0 were created. All the initial plans were recalculated by changing the DTF parameter from 1.0 to 3.0 in increments of 0.1. Then, DTF's impact on delivery efficiency and plan quality was evaluated. Treatment time and modulation factor increased monotonically with increasing DTF. Increasing the DTF by 0.1 increased the treatment time and modulation factor by almost 10%. This relationship was similar for all treatment sites. Conformity index (CI), homogeneity index, and organ at risk doses were improved compared to plans with a DTF of 1.0, except for the CI in the lung cancer case. However, the improvement in most indices ceased at a certain DTF; nevertheless, treatment time continued to increase following an increase in DTF. DTF is a critical parameter for improving the quality of tomotherapy plans.

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.

Effectiveness of robust optimization against geometric uncertainties in TomoHelical planning for prostate cancer.

BACKGROUND: Geometrical uncertainties in patients can severely affect the quality of radiotherapy. PURPOSE: We evaluated the dosimetric efficacy of robust optimization for helical intensity-modulated radiotherapy (IMRT) planning in the presence of patient setup uncertainty and anatomical changes. METHODS: Two helical IMRT plans for 10 patients with localized prostate cancer were created using either minimax robust optimization (robust plan) or a conventional planning target volume (PTV) margin approach (PTV plan). Plan robustness was evaluated by creating perturbed dose plans with setup uncertainty from isocenter shifts and anatomical changes due to organ variation. The magnitudes of the geometrical uncertainties were based on the patient setup uncertainty considered during robust optimization, which was identical to the PTV margin. The homogeneity index, and target coverage (TC, defined as the V100% of the clinical target volume), and organs at risk (OAR; rectum and bladder) doses were analyzed for all nominal and perturbed plans. A statistical t-test was performed to evaluate the differences between the robust and PTV plans. RESULTS: Comparison of the nominal plans showed that the robust plans had lower OAR doses and a worse homogeneity index and TC than the PTV plans. The evaluations of robustness that considered setup errors more than the PTV margin demonstrated that the worst-case perturbed scenarios for robust plans had significantly higher TC while maintaining lower OAR doses. However, when anatomical changes were considered, improvement in TC from robust optimization was not observed in the worst-case perturbed plans. CONCLUSIONS: For helical IMRT planning in localized prostate cancer, robust optimization provides benefits over PTV margin-based planning, including better OAR sparing, and increased robustness against systematic patient-setup errors.

[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.

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.

[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.

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.

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.

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.

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.

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.

Brief exposure of skin to near-infrared laser augments early vaccine responses.

Rapid establishment of herd immunity with vaccination is effective to combat emerging infectious diseases. Although the incorporation of adjuvant and intradermal (ID) injection could augment early responses to the vaccine, the current chemical or biological adjuvants are inappropriate for this purpose with their side effects and high reactogenicity in the skin. Recently, a near-infrared (NIR) laser has been shown to augment the immune response to ID vaccination and could be alternatively used for mass vaccination programs. Here, we determined the effect of NIR laser as well as licensed chemical adjuvants on the immunogenicity 1, 2, and 4 weeks after ID influenza vaccination in mice. The NIR laser adjuvant augmented early antibody responses, while the widely used alum adjuvant induced significantly delayed responses. In addition, the oil-in-water and alum adjuvants, but not the NIR laser, elicited escalated TH2 responses with allergenic immunoglobulin E (IgE) responses. The effect of the NIR laser was significantly suppressed in the basic leucine zipper transcription factor ATF-like 3 (Batf3) knockout mice, suggesting a critical role of the cluster of differentiation 103+ (CD103)+ dendritic cells. The current preliminary study suggests that NIR laser adjuvant is an alternative strategy to chemical and biological agents to timely combat emerging infectious diseases. Moreover, its immunomodulatory property could be used to enhance the efficacy of immunotherapy for allergy and cancer.

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.