Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore.

Inhibition of glucosylceramide synthase (GCS) is a major therapeutic strategy for Gaucher's disease and has been suggested as a potential target for treating Parkinson's disease. Herein, we report the discovery of novel brain-penetrant GCS inhibitors. Assessment of the structure-activity relationship revealed a unique pharmacophore in this series. The lipophilic ortho-substituent of aromatic ring A and the appropriate directionality of aromatic ring B were key for potency. Optimization of the absorption, distribution, metabolism, elimination, toxicity (ADMETox) profile resulted in the discovery of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based scaffold hopping was performed to mitigate safety concerns associated with T-036. The ring opening of T-036 resulted in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent manner in the plasma and cortex of mice. Finally, we discuss the structural aspects of the compounds that impart a unique inhibition mode and lower the cardiovascular risk.

Joint Environmental Radiation Survey by JAEA and KAERI Around the Fukushima Daiichi Nuclear Power Plant: Performance of Mobile Gamma-Ray Spectrometry Using Backpack and Carborne Survey Platforms.

ABSTRACT: According to the implementing arrangement between the Japan Atomic Energy Agency (JAEA) and the Korea Atomic Energy Research Institute (KAERI) in the field of radiation protection and environmental radiation monitoring, a joint survey program was performed to assess ground deposition of radioactive cesium in areas surrounding the Fukushima Daiichi Nuclear Power Plants. The purpose of this joint survey was to evaluate the field applications of the developed survey systems and methodologies. Understanding the performance of each system within a cesium-deposited contaminated zone is important for ensuring an appropriate response following a nuclear accident. The results of the measured ambient dose rates determined using each survey method were compared. Two kinds of survey system were used in the mobile gamma-ray spectrometry, which were MARK-M1 (Monitoring of Ambient Radiation of KAERI-the 1st Multipurpose system) based on two LaBr3(Ce) detectors of KAERI and KURAMA-II (Kyoto University Radiation Mapping - II) system with one CsI(Tl) detector of JAEA. First, mobile gamma-ray spectrometry using a backpack survey platform was conducted to assess the distribution of dose rates around specific survey sites, which were expected to be slightly contaminated by radioactive cesium in Minamisoma and Tomioka. A carborne survey using two gamma-ray spectrometers loaded inside a vehicle was successfully conducted to compare the measured dose rates in routes from site to site and verify evaluation methods, including attenuation correction.

A Novel Orthotopic Liver Cancer Model for Creating a Human-like Tumor Microenvironment.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. This study aims to develop a new method to generate an HCC mouse model with a human tumor, and imitates the tumor microenvironment (TME) of clinical patients. Here, we have generated functional, three-dimensional sheet-like human HCC organoids in vitro, using luciferase-expressing Huh7 cells, human iPSC-derived endothelial cells (iPSC-EC), and human iPSC-derived mesenchymal cells (iPSC-MC). The HCC organoid, capped by ultra-purified alginate gel, was implanted into the disrupted liver using an ultrasonic homogenizer in the immune-deficient mouse, which improved the survival and engraftment rate. We successfully introduced different types of controllable TME into the model and studied the roles of TME in HCC tumor growth. The results showed the role of the iPSC-EC and iPSC-MC combination, especially the iPSC-MC, in promoting HCC growth. We also demonstrated that liver fibrosis could promote HCC tumor growth. However, it is not affected by non-alcoholic fatty liver disease. Furthermore, the implantation of HCC organoids to humanized mice demonstrated that the immune response is important in slowing down tumor growth at an early stage. In conclusion, we have created an HCC model that is useful for studying HCC development and developing new treatment options in the future.

Investigation of Clinical Safety of Human iPS Cell-Derived Liver Organoid Transplantation to Infantile Patients in Porcine Model.

Transplantation of liver organoids has been investigated as a treatment alternative to liver transplantation for chronic liver disease. Transportal approach can be considered as a method of delivering organoids to the liver. It is important to set the allowable organoid amount and verify translocation by intraportal transplantation. We first examined the transplantation tolerance and translocation of porcine fetal liver-derived allogeneic organoids using piglets. Fetal liver-derived organoids generated from the Kusabira Orange-transduced pig were transplanted to the 10-day-old piglet liver through the left branch of the portal vein. All recipients survived without any observable adverse events. In contrast, both local and main portal pressures increased transiently during transplantation. In necropsy samples, Kusabira Orange-positive donor cells were detected primarily in the target lobe of the liver and partly in other areas, including the lungs and brain. As we confirmed the transplantation allowance by porcine fetal liver-derived organoids, we performed intraportal transplantation of human-induced pluripotent stem cell (iPSC)-derived liver organoid, which we plan to use in clinical trials, and portal pressure and translocation were investigated. Human iPSC-derived liver organoids were transplanted into the same 10-day-old piglet. Portal hypertension and translocation of human iPSC-derived liver organoids to the lungs were observed in one of two transplanted animals. Translocation occurred in the piglet in which patent ductus venosus (PDV) was observed. Therefore, a 28-day-old piglet capable of surgically ligating PDV was used, and after the PDV was ligated, human iPSC-derived liver organoids with the amount of which is scheduled in clinical trials were transplanted. This procedure inhibited the translocation of human iPSC-derived liver organoids to extrahepatic sites without no portal hypertension. In conclusion, human iPSC-derived liver organoids can be safely transplanted through the portal vein. Ligation of the ductus venosus prior to transplantation was effective in inhibiting extrahepatic translocation in newborns and infants.

Effect of cholecalciferol on serum hepcidin and parameters of anaemia and CKD-MBD among haemodialysis patients: a randomized clinical trial.

In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563 . UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E .

Optimizing long-term monitoring of radiation air-dose rates after the Fukushima Daiichi Nuclear Power Plant.

Radiation air dose rates near the Fukushima Daiichi Nuclear Power Plant (FDNPP) have been steadily decreasing over the past eight years since the release of radioactive elements in March 2011. Currently, the radiation monitoring program is expected to transition to long-term monitoring after most of the remediation activities are completed. The main long-term monitoring objectives are to (1) confirm the continuing reduction of contaminant and hazard levels, (2) provide assurance for the public, (3) accumulate the basic datasets for scientific knowledge and future preparation, and (4) detect changes or anomalies in contaminant mobility (if they occur), or any unexpected processes or events. In this work, we have developed a methodology for optimizing the monitoring locations of radiation air dose-rate monitoring. Our approach consists of three steps in order to determine monitoring locations in a systematic manner: (1) prioritizing the critical locations, such as schools or regulatory requirement locations, (2) diversifying locations that cover the key environmental controls that are known to influence contaminant mobility and distributions, and (3) capturing the heterogeneity of radiation air-dose rates across the domain. For the second step, we use a Gaussian mixture model to identify the representative locations among multiple environmental variables, such as elevation and land-cover types. For the third step, we use a Gaussian process model to capture and estimate the heterogeneity of air-dose rates across the domain. Employing an integrated dose-rate map derived from Bayesian geostatistical methods as a reference map, we distribute the monitoring locations in such a way as to capture the heterogeneity of the reference map. Our results have shown that this approach allows us to select monitoring locations in a systematic manner such that the heterogeneity of air dose rates is captured by the minimal number of monitoring locations.

Rational discovery of a highly novel and selective mTOR inhibitor.

Aided by Structure Based Drug Discovery (SBDD), we rapidly designed a highly novel and selective series of mTOR inhibitors. This chemotype conveys exquisite kinase selectivity, excellent in vitro and in vivo potencies and ADME safety profiles. These compounds could serve as good tools to explore the potential of TORC inhibition in various human diseases.

The deposition densities of radiocesium and the air dose rates in undisturbed fields around the Fukushima Dai-ichi nuclear power plant; their temporal changes for five years after the accident.

The deposition densities of radiocesium and the air dose rates were repeatedly measured in a large number of undisturbed fields within the 80 km zone that surrounds the Fukushima Dai-ichi Nuclear Power Plant site between 2011 and 2016, and features of their temporal changes were clarified. The average air dose rate excluding background radiation in this zone decreased to about 20% of the initial value during the period from June 2011 to August 2016, which was essentially a result of the radioactive decay of 134Cs with a half-life of 2.06 y. The air dose rate reduction was faster than that expected from the decay of radiocesium by a factor of about two, with most of this reduction being attributed to the penetration of radiocesium into the soil. The average deposition densities of 134Cs and 137Cs in fields that were not decontaminated were found to have decreased nearly according to their expected radioactive decay, which indicated that the movement of radiocesium in the horizontal direction was relatively small. The effect of decontamination was apparently observed in the measurements of air dose rates and deposition densities. Nominally, the average air dose rates in the measurement locations were reduced by about 20% by decontamination and other human activities, of which accurate quantitative analysis is and continue to be a challenge. In this paper, new original data obtained during 2013-2016 were added to the previously reported data collected up to 2012, and it is discussed throughout.

Guidance for in situ gamma spectrometry intercomparison based on the information obtained through five intercomparisons during the Fukushima mapping project.

Five intercomparisons of in situ gamma spectrometry by 6-7 participating teams were conducted between December 2011 and August 2015 at sites in Fukushima Prefecture that were affected by the fallout from the accident at the Fukushima Dai-ichi Nuclear Power Plant in March 2011. The evaluated deposition densities agreed within 5% and 4% in terms of the coefficient of variation for radiocesium (134Cs and 137Cs) and 40K, respectively, and the ratio of 134Cs/137Cs in deposition density agreed within 1% in terms of the coefficient of variation, by our best achievement through five intercomparisons. Two different methods for intercomparison were conducted: 1) simultaneous measurements in a narrow area within a 3 m radius; and 2) sequential measurements at an identical point. In a comparison between the two methods at a site where radiocesium was almost homogeneously distributed, no significant difference was observed between the results. The guidance for intercomparison method was proposed based on our experience, and are expected to be used effectively to ensure the reliability of in situ spectrometry.

Summary of temporal changes in air dose rates and radionuclide deposition densities in the 80 km zone over five years after the Fukushima Nuclear Power Plant accident.

We summarized temporal changes in air dose rates and radionuclide deposition densities over five years in the 80 km zone based on large-scale environmental monitoring data obtained continuously after the Fukushima Nuclear Power Plant (NPP) accident, including those already reported in the present and previous special issues. After the accident, multiple radionuclides deposited on the ground were detected over a wide area; radiocesium was found to be predominantly important from the viewpoint of long-term exposure. The relatively short physical half-life of 134Cs (2.06 y) has led to considerable reductions in air dose rates. The reduction in air dose rates owing to the radioactive decay of radiocesium was more than 60% over five years. Furthermore, the air dose rates in environments associated with human lives decreased at a considerably faster rate than expected for radioactive decay. The average air dose rate originating from the radiocesium deposited in the 80 km zone was lower than that predicted from radioactive decay by a factor of 2-3 at five years after the accident. Vertical penetration of radiocesium into the ground contributed greatly to the reduction in air dose rate because of an increase in the shielding of gamma rays; the estimated average reduction in air dose rate was approximately 25% with penetration compared to that without penetration. The average air dose rate measured in undisturbed fields in the 80 km zone was estimated to be reduced owing to decontamination by approximately 20% compared to that without decontamination. The average deposition density of radiocesium in undisturbed fields has decreased owing to radioactive decay, indicating that the migration of radiocesium in the horizontal direction has generally been slow. Nevertheless, in human living environments, horizontal radiocesium movement is considered to contribute significantly to the reduction in air dose rate. The contribution of horizontal radiocesium movement to the decrease in air dose rate was estimated to vary by up to 30% on average. Massive amounts of environmental data were used in extended analyses, such as the development of a predictive model or integrated air dose rate maps according to different measurement results, which facilitated clearer characterization of the contamination conditions. Ecological half-lives were evaluated in several studies by using a bi-exponential model. Short-term ecological half-lives were shorter than one year in most cases, while long-term ecological half-lives were different across the studies. Even though the general tendency of decrease in air dose rates and deposition densities in the 80 km zone were elucidated as summarized above, their trend was found to vary significantly according to location. Therefore, site-specific analysis is an important task in the future.

The Regenerative Effect of Portal Vein Injection of Liver Organoids by Retrorsine/Partial Hepatectomy in Rats.

In this study, we reveal that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage. The liver organoids significantly reconstituted the hepatocytes; hence, the liver was significantly enlarged in this group, compared to the monolayer cell transplantation group in the retrorsine/partial hepatectomy (RS/PH) model. In the liver organoid transplantation group, the bile ducts were located in the donor area and connected to the recipient bile ducts. Thus, the rate of bile reconstruction in the liver was significantly higher compared to that in the monolayer group. By transplanting liver organoids, we saw a level of 70% replacement of the damaged liver. Consequently, in the transplantation group, diminished ductular reaction and a decrease of placental glutathione S-transferase (GST-p) precancerous lesions were observed. After trans-portal injection, the human induced pluripotent stem cell (hiPSC)-derived liver organoids revealed no translocation outside the liver; in contrast, the monolayer cells had spread to the lungs. The hiPSC-derived liver organoids were attached to the liver in the immunodeficient RS/PH rats. This study clearly demonstrates that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage in rats.

Decreasing trend of ambient dose equivalent rates over a wide area in eastern Japan until 2016 evaluated by car-borne surveys using KURAMA systems.

As part of the investigation of the distribution of ambient dose equivalent rates around the Fukushima Dai-ichi Nuclear Power Plant (FDNPP), car-borne surveys using Kyoto University RAdiation MApping (KURAMA) systems have been conducted over a wide area in eastern Japan since 2011. The enormous volume of measurement data collected until 2016, including those until 2012 which were reported in the previous paper, was analyzed, and dependencies of the decreasing trend of the dose rates in regions within 80 km of the FDNPP on land-use categories, evacuation order areas and magnitude of the dose rates were examined. The air dose rates within 80 km of the FDNPP tended to decrease considerably with respect to the physical decay of radiocaesium. The decrease of the dose rate in the "forest" was slower than its decrease in other regions, while that in "urban area" was the fastest. The decrease in the air dose rate from 2011 was the fastest outside the evacuation order area until 2015, and it was the slowest in the "difficult-to-return zone". However, the decreasing trend starting from 2013 showed that the decrease in the "zone in preparation for the lifting of the evacuation order" and in the "residence restriction area" was the fastest. It was found that the air dose rates decreased depending on the magnitude of the dose rates and elapsed time from the FDNPP accident, i.e. the decrease in air dose rates in areas with relatively low dose ranges (such as 0.2-0.5 µSv/h) was the largest during a period relatively early after the accident, and the decreasing rate in the dose rate ranges of 1.9-3.8 and 3.8-9.5 µSv/h were the fastest after 2013. The averaged ratios were analyzed to obtain the ecological half-lives of the fast and slow decay components, and those in whole area within 80 km of FDNPP were estimated to be 0.44 ±â€¯0.05 y and 6.7 ±â€¯1 y, respectively. The ecological half-lives with respect to the land use categories, evacuation order areas and magnitude of the dose rates were also evaluated. The decrease in the dose rates obtained by the car-borne survey was larger than that obtained on flat ground with few disturbances using the NaI(Tl) survey meter during approximately 1.5 y after the FDNPP accident. Thereafter, the difference of decreasing tendencies in the air dose rates between both the measurements was negligibly small, with the ratio of dose rates by the car-borne survey to those by the fixed-point measurement of 0.72-0.77.

Characterizing regional-scale temporal evolution of air dose rates after the Fukushima Daiichi Nuclear Power Plant accident.

In this study, we quantify the temporal changes of air dose rates in the regional scale around the Fukushima Dai-ichi Nuclear Power Plant in Japan, and predict the spatial distribution of air dose rates in the future. We first apply the Bayesian geostatistical method developed by Wainwright et al. (2017) to integrate multiscale datasets including ground-based walk and car surveys, and airborne surveys, all of which have different scales, resolutions, spatial coverage, and accuracy. This method is based on geostatistics to represent spatial heterogeneous structures, and also on Bayesian hierarchical models to integrate multiscale, multi-type datasets in a consistent manner. We apply this method to the datasets from three years: 2014 to 2016. The temporal changes among the three integrated maps enables us to characterize the spatiotemporal dynamics of radiation air dose rates. The data-driven ecological decay model is then coupled with the integrated map to predict future dose rates. Results show that the air dose rates are decreasing consistently across the region. While slower in the forested region, the decrease is particularly significant in the town area. The decontamination has contributed to significant reduction of air dose rates. By 2026, the air dose rates will continue to decrease, and the area above 3.8 µSv/h will be almost fully contained within the non-residential forested zone.

Decreasing trend of ambient dose equivalent rates over a wide area in eastern Japan until 2016 evaluated by car-borne surveys using KURAMA systems.

As part of the investigation of the distribution of ambient dose equivalent rates around the Fukushima Dai-ichi Nuclear Power Plant (FDNPP), car-borne surveys using Kyoto University RAdiation MApping (KURAMA) systems have been conducted over a wide area in eastern Japan since 2011. The enormous volume of measurement data collected until 2016, including those until 2012 which were reported in the previous paper, was analyzed, and dependencies of the decreasing trend of the dose rates in regions within 80 km of the FDNPP on land-use categories, evacuation order areas and magnitude of the dose rates were examined. The air dose rates within 80 km of the FDNPP tended to decrease considerably with respect to the physical decay of radiocaesium. The decrease of the dose rate in the "forest" was slower than its decrease in other regions, while that in "urban area" was the fastest. The decrease in the air dose rate from 2011 was the fastest outside the evacuation order area until 2015, and it was the slowest in the "difficult-to-return zone". However, the decreasing trend starting from 2013 showed that the decrease in the "zone in preparation for the lifting of the evacuation order" and in the "residence restriction area" was the fastest. It was found that the air dose rates decreased depending on the magnitude of the dose rates and elapsed time from the FDNPP accident, i.e. the decrease in air dose rates in areas with relatively low dose ranges (such as 0.2-0.5 µSv/h) was the largest during a period relatively early after the accident, and the decreasing rate in the dose rate ranges of 1.9-3.8 and 3.8-9.5 µSv/h were the fastest after 2013. The averaged ratios were analyzed to obtain the ecological half-lives of the fast and slow decay components, and those in whole area within 80 km of FDNPP were estimated to be 0.44 ±â€¯0.05 y and 6.7 ±â€¯1 y, respectively. The ecological half-lives with respect to the land use categories, evacuation order areas and magnitude of the dose rates were also evaluated. The decrease in the dose rates obtained by the car-borne survey was larger than that obtained on flat ground with few disturbances using the NaI(Tl) survey meter during approximately 1.5 y after the FDNPP accident. Thereafter, the difference of decreasing tendencies in the air dose rates between both the measurements was negligibly small, with the ratio of dose rates by the car-borne survey to those by the fixed-point measurement of 0.72-0.77.

Characterizing regional-scale temporal evolution of air dose rates after the Fukushima Daiichi Nuclear Power Plant accident.

In this study, we quantify the temporal changes of air dose rates in the regional scale around the Fukushima Dai-ichi Nuclear Power Plant in Japan, and predict the spatial distribution of air dose rates in the future. We first apply the Bayesian geostatistical method developed by Wainwright et al. (2017) to integrate multiscale datasets including ground-based walk and car surveys, and airborne surveys, all of which have different scales, resolutions, spatial coverage, and accuracy. This method is based on geostatistics to represent spatial heterogeneous structures, and also on Bayesian hierarchical models to integrate multiscale, multi-type datasets in a consistent manner. We apply this method to the datasets from three years: 2014 to 2016. The temporal changes among the three integrated maps enables us to characterize the spatiotemporal dynamics of radiation air dose rates. The data-driven ecological decay model is then coupled with the integrated map to predict future dose rates. Results show that the air dose rates are decreasing consistently across the region. While slower in the forested region, the decrease is particularly significant in the town area. The decontamination has contributed to significant reduction of air dose rates. By 2026, the air dose rates will continue to decrease, and the area above 3.8 µSv/h will be almost fully contained within the non-residential forested zone.

Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders.

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3',5'-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.

Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders.

Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.

Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders.

Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-N-((1R)-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (38a), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of 38a bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound 38a significantly elevated 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization.

Spinal Cord Ischemia Secondary to Epidural Metastasis from Small Cell Lung Carcinoma.

BACKGROUND Spinal cord ischemia is an uncommon event that is mainly caused by dissociation of the ascending aorta as a complication after aortic surgery. Spinal arteries can develop collateral circulation; therefore, the frequency of spinal infarction is about 1% of that in the brain. Few cases of spinal cord ischemia developing in the course of lung cancer have been reported. CASE REPORT We presented the case of a 56-year-old man with small cell lung carcinoma, cT4N2M1a (stage IV). He was treated with irradiation and 2 courses of platinum and etoposide combination chemotherapy. He complained of back pain followed by quadriplegia and sensory disturbance after cessation of chemotherapy. With a diagnosis of spinal cord metastasis, steroids were administered. However, diaphragmatic paralysis appeared a few hours later. He was started on palliative care and died after 6 days. Autopsy showed epidural metastasis and spinal ischemia at the C5 level. CONCLUSIONS Epidural metastasis can compress the spinal artery and cause circulatory disorders. Spinal cord ischemia should be considered in patients with rapid paralysis in the course of lung cancer.

Measurements of air dose rates in and around houses in the Fukushima Prefecture in Japan after the Fukushima accident.

Measurements of air dose rates for 192 houses in a less contaminated area (<0.5 µSv h-1) of the Fukushima Prefecture in Japan were conducted in both living rooms and/or bedrooms using optically stimulated luminescence (OSL) dosimeters and around the houses via a man-borne survey at intervals of several meters. The relation of the two air dose rates (inside and outside) for each house, including the background from natural radionuclides, was divided into several categories, determined by construction materials (light and heavy) and floor number, with the dose reduction factors being expressed as the ratio of the dose inside to that outside the house. For wooden and lightweight steel houses (classed as light), the dose rates inside and outside the houses showed a positive correlation and linear regression with a slope-intercept form due to the natural background, although the degree of correlation was not very high. The regression coefficient, i.e., the average dose reduction factor, was 0.38 on the first floor and 0.49 on the second floor. It was found that the contribution of natural radiation cannot be neglected when we consider dose reduction factors in less contaminated areas. The reductions in indoor dose rates are observed because a patch of ground under each house is not contaminated (this is the so-called uncontaminated effect) since the shielding capability of light construction materials is typically low. For reinforced steel-framed concrete houses (classed as heavy), the dose rates inside the houses did not show a correlation with those outside the houses due to the substantial shielding capability of these materials. The average indoor dose rates were slightly higher than the arithmetic mean value of the outdoor dose rates from the natural background because concrete acts as a source of natural radionuclides. The characteristics of the uncontaminated effect were clarified through Monte Carlo simulations. It was found that there is a great variation in air dose rates even within one house, depending on the height of the area and its closeness to the outside boundary. Measurements of outdoor dose rates required consideration of local variations depending on the environment surrounding each house. The representative value was obtained from detailed distributions of air dose rates around the house, as measured by a man-borne survey. Therefore, it is imperative to recognize that dose reduction factors fluctuate in response to various factors such as the size and shape of a house, construction materials acting as a shield and as sources, position (including height) within a room, floor number, total number of floors, and surrounding environment.