Prevention and treatment of radiotherapy-induced side effects

Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. High-precision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery

Identification of candidate genes affecting Delta9-tetrahydrocannabinol biosynthesis in Cannabis sativa.

RNA isolated from the glands of a Delta(9)-tetrahydrocannabinolic acid (THCA)-producing strain of Cannabis sativa was used to generate a cDNA library containing over 100 000 expressed sequence tags (ESTs). Sequencing of over 2000 clones from the library resulted in the identification of over 1000 unigenes. Candidate genes for almost every step in the biochemical pathways leading from primary metabolites to THCA were identified. Quantitative PCR analysis suggested that many of the pathway genes are preferentially expressed in the glands. Hexanoyl-CoA, one of the metabolites required for THCA synthesis, could be made via either de novo fatty acids synthesis or via the breakdown of existing lipids. qPCR analysis supported the de novo pathway. Many of the ESTs encode transcription factors and two putative MYB genes were identified that were preferentially expressed in glands. Given the similarity of the Cannabis MYB genes to those in other species with known functions, these Cannabis MYBs may play roles in regulating gland development and THCA synthesis. Three candidates for the polyketide synthase (PKS) gene responsible for the first committed step in the pathway to THCA were characterized in more detail. One of these was identical to a previously reported chalcone synthase (CHS) and was found to have CHS activity. All three could use malonyl-CoA and hexanoyl-CoA as substrates, including the CHS, but reaction conditions were not identified that allowed for the production of olivetolic acid (the proposed product of the PKS activity needed for THCA synthesis). One of the PKS candidates was highly and specifically expressed in glands (relative to whole leaves) and, on the basis of these expression data, it is proposed to be the most likely PKS responsible for olivetolic acid synthesis in Cannabis glands

Combined association of cognitive impairment and poor oral health on mortality risk in older adults: Results from the NHANES with 15 years of follow-up

BACKGROUND: Cognitive impairment and poor oral health are frequently seen among older adults. Both conditions have been identified as risk factors for mortality. However, the combined associations of cognitive impairment and poor oral health with mortality have not been well studied and are therefore the aim of this cohort study. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (1999–2002) linked with mortality data obtained from the 2015 public-use linked mortality file. Cognitive impairment was defined as a digit symbol substitution test score lower than the lowest quartile. Oral health status was assessed based on presence of untreated caries, moderate to severe periodontitis, and edentulism. The combined effects of caries/periodontitis or edentulism and cognitive impairment on all-cause and cardiometabolic mortality were examined using the Cox proportional hazard models after adjusting for potential confounders including demographic characteristics, lifestyle, biomarkers, and comorbidities. RESULTS: In total, 1973 participants were enrolled in the prospective study. At a median follow-up of 13.4 years, 978 participants had died (264 deaths because of cardiometabolic disease). Cognitive impairment, periodontitis, and edentulism were each found to be significant predictors of all-cause mortality. Caries, however, was not significantly related to mortality. When analyzing these predictors in combination, a diagnosis of cognitive impairment and periodontitis was associated with an 83.1% increase in all-cause mortality risk and an 87.7% increase in cardiometabolic mortality risk compared with healthy controls. Similarly, the risk for all-cause mortality was highest in cases where impaired cognition and edentulism co-occurred (adjusted hazard ratio = 1.701, 1.338–2.161). CONCLUSION: Concomitant presence of cognitive impairment and periodontitis or edentulism can be associated with a higher risk of mortality among older U.S. adults

Ultrafast manipulation of mirror domain walls in a charge density wave

Domain walls (DWs) are singularities in an ordered medium that often host exotic phenomena such as charge ordering, insulator-metal transition, or superconductivity. The ability to locally write and erase DWs is highly desirable, as it allows one to design material functionality by patterning DWs in specific configurations. We demonstrate such capability at room temperature in a charge density wave (CDW), a macroscopic condensate of electrons and phonons, in ultrathin 1T-TaS$_2$. A single femtosecond light pulse is shown to locally inject or remove mirror DWs in the CDW condensate, with probabilities tunable by pulse energy and temperature. Using time-resolved electron diffraction, we are able to simultaneously track anti-synchronized CDW amplitude oscillations from both the lattice and the condensate, where photo-injected DWs lead to a red-shifted frequency. Our demonstration of reversible DW manipulation may pave new ways for engineering correlated material systems with light

LANDSAT-D investigations in snow hydrology

Work undertaken during the contract and its results are described. Many of the results from this investigation are available in journal or conference proceedings literature - published, accepted for publication, or submitted for publication. For these the reference and the abstract are given. Those results that have not yet been submitted separately for publication are described in detail. Accomplishments during the contract period are summarized as follows: (1) analysis of the snow reflectance characteristics of the LANDSAT Thematic Mapper, including spectral suitability, dynamic range, and spectral resolution; (2) development of a variety of atmospheric models for use with LANDSAT Thematic Mapper data. These include a simple but fast two-stream approximation for inhomogeneous atmospheres over irregular surfaces, and a doubling model for calculation of the angular distribution of spectral radiance at any level in an plane-parallel atmosphere; (3) incorporation of digital elevation data into the atmospheric models and into the analysis of the satellite data; and (4) textural analysis of the spatial distribution of snow cover

Profiling the educational value of computer games

There are currently a number of suggestions for educators to include computer games in formal teaching and learning contexts. Educational value is based on claims that games promote the development of complex learning. Very little research, however, has explored what features should be present in a computer game to make it valuable or conducive to learning. We present a list of required features for an educational game to be of value, informed by two studies, which integrated theories of Learning Environments and Learning Styles. A user survey showed that some requirements were typical of games in a particular genre, while other features were present across all genres. The paper concludes with a proposed framework of games and features within and across genres to assist in the design and selection of games for a given educational scenari

Combined association of cognitive impairment and poor oral health on mortality risk in older adults:results from the NHANES with 15 years of follow-up

BACKGROUND: Cognitive impairment and poor oral health are frequently seen among older adults. Both conditions have been identified as risk factors for mortality. However, the combined associations of cognitive impairment and poor oral health with mortality have not been well studied and are therefore the aim of this cohort study. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (1999-2002) linked with mortality data obtained from the 2015 public-use linked mortality file. Cognitive impairment was defined as a digit symbol substitution test score lower than the lowest quartile. Oral health status was assessed based on presence of untreated caries, moderate to severe periodontitis, and edentulism. The combined effects of caries/periodontitis or edentulism and cognitive impairment on all-cause and cardiometabolic mortality were examined using the Cox proportional hazard models after adjusting for potential confounders including demographic characteristics, lifestyle, biomarkers, and comorbidities. RESULTS: In total, 1,973 participants were enrolled in the prospective study. At a median follow-up of 13.4 years, 978 participants had died (264 deaths due to cardiometabolic disease). Cognitive impairment, periodontitis, and edentulism were each found to be significant predictors of all-cause mortality. Caries, however, was not significantly related to mortality. When analyzing these predictors in combination, a diagnosis of cognitive impairment and periodontitis was associated with an 83.1% increase in all-cause mortality risk and an 87.7% increase in cardiometabolic mortality risk compared with healthy controls. Similarly, the risk for all-cause mortality was highest in cases where impaired cognition and edentulism co-occurred (adjusted hazard ratio = 1.701, 1.338-2.161). CONCLUSION: Concomitant presence of cognitive impairment and periodontitis or edentulism can be associated with a higher risk of mortality among older U.S. adults

Development of a Flood Warning Simulation System:A Case Study of 2007 Tewkesbury Flood

Many flood warning systems were developed for 2D environments and limited on specific flood hazard. With the purpose of overcoming these disadvantages, it is necessary to propose new methodologies and techniques for 3D real time flood simulation. In this paper, a novel flood hazard warning system has been proposed. It describes and defines the relationship between the different parts of the simulation system in order to offer not only numeric data or figures, but also more meaningful and appealing 3D visual information. Consequently, the performance of this simulation system depends on the quality of the three sub systems: 3D real world modelling system with GIS data, 3D environment reconstruction system and 3D flood simulation system. A new flooding model has been developed which can handle dynamic flood behaviour and predict inundation areas in real time. In order to validate our flood warning system, the region of Tewkesbury in England has been simulated with a potential flood. The flood spreading process is shown during different time and the detailed inundation area is presented for further disaster evaluation. The study achieved two main objectives: implementing a useful flood simulation with real world model and reconstructed environment for flood hazard warning; producing a friendly simulation system interface for either a decision maker or experienced user

Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis

CHOP turns on ERO1-α to release calcium via IP3R and trigger cell death in response to ER stress

Periodontitis and cognitive impairment in older adults:The mediating role of mitochondrial dysfunction

Background: Increased attention has been focused on the associations of periodontal disease with the onset and progression of cognitive impairment. Although the associations are likely to be multifactorial, few studies have explored the role of mitochondrial dysfunction in the periodontitis-dementia link. Methods: Cross-sectional data of 1,883 participants aged ≥60 years in the National Health and Nutrition Examination Survey 2011‒2014 were analyzed. The following data were collected: 1) general information on sociodemographic, behavioral, and health-related factors; 2) periodontal status (mean attachment loss [AL] and mean probing depth [PD]); 3) mitochondrion-derived biomarker of mitochondrial dysfunction (blood sample concentration of methylmalonic acid [MMA]); 4) cognitive function (Consortium to Establish a Registry for Alzheimer's disease immediate recall [CERAD-IR] and delay recall [CERAD-DR], animal fluency test, and digit symbol substitution test [DSST]). Mediation analysis weighted for complex survey design was used to assess the effect of MMA on the association of periodontal status with cognitive function after adjusting for potential confounders. Results: Participants with Stage III and IV periodontitis had lower scores on cognitive performance and higher MMA levels than those with Stages I/II periodontitis. Circulating MMA was significantly associated with CERAD-DR (weighted β [SE] = −0.076 [0.011]) and DSST (weighted β [SE] = −0.039 [0.009]), which mediated 9.9% and 6.0% of the total association of mean PD with cognitive function. Moreover, MMA mediated 11.7% and 5.8% of the association of mean AL with CERAD-DR and DSST, respectively. Conclusion: The findings suggest that MMA, a biomarker of mitochondrial dysfunction, plays a mediating role in the link between periodontitis and cognitive impairment in older adults aged ≥60 years