Identification of biomarkers for the prediction of radiation toxicity in prostate cancer patients

The success of radiotherapy in tumour control depends on the total dose given. However, the tolerance of the normal tissues surrounding the tumour limits this dose. It is not known why some patients develop radiation toxicity and, currently, it is not possible to predict before treatment which patients will experience adverse effects. Thus, there is an unmet clinical need for a new test to identify patients at risk of radiation toxicity. The aim of this study was to determine if spectral variations in blood lymphocytes from PCa patients may suggest Raman spectral bands that could be used in future research to identify spectral features associated with radiosensitivity. Blood samples were collected retrospectively from 42 patients enrolled on the Cancer Trials Ireland ICORG 08-17 study who had undergone radiotherapy for prostate cancer and had shown either severe or no/minimal late radiation toxicity in follow-up. Radiation response was assessed following in-vitro irradiation using Raman micro-spectroscopy in addition to the G2 chromosomal radiosensitivity assay and the γH2AX DNA damage assay. A partial least squares discriminant analysis model was developed to classify patients using known radiation toxicity scores. Following this retrospective study, blood samples were collected prospectively from 51 patients also enrolled on the ICORG 08- 17 study. These samples were collected prior to radiotherapy and these patients were categorised based on severe or no/minimal late radiation toxicity in follow-up. Radiation response was assessed following in-vitro irradiation using Raman micro-spectroscopy in addition to the G2 chromosomal radiosensitivity assay and the γH2AX DNA damage assay. A partial least squares discriminant analysis model was developed to predict radiation toxicity. Finally, blood samples were collected prospectively prior to radiotherapy from another 30 patients enrolled on the Northern Ireland Cancer Trials Centre SPORT study for prostate cancer and these patients were also categorised based on severe or no/minimal late radiation toxicity in follow-up. Radiation response was assessed following in-vitro irradiation using Raman micro-spectroscopy in addition to the citrulline assay. A partial least squares discriminant analysis model was again developed to predict radiation toxicity. Prediction of radiation toxicity outcome could not be achieved based on late radiation toxicity in the cohort of prostate cancer patients enrolled on the ICORG 08-17 study, but some success in predicting radiation toxicity could be achieved based on late radiation toxicity in the cohort of prostate cancer patients enrolled on the Northern Ireland Cancer Trials Centre SPORT study. The patients from the ICORG 08-17 study will be followed up at 6 monthly intervals until Year 9 however, and those from the SPORT study will be followed up every 6 months for up to 5 years with a minimum annual follow-up from 5- 10 years, allowing the models to be updated as patient clinical status changes. In the future, this technology may have potential to lead to individualized patient radiotherapy by identifying patients that are at risk of radiation toxicity

Making UK aid work: why scrutiny is key – and how to achieve it

The effectiveness of UK aid spending is reliant on the government’s ability to exercise meaningful oversight over spending decisions. This oversight is currently lacking, explain Ambreena Manji and Daniel Cullen, putting the effectiveness of aid spending at risk

SEM/EDS Observations of Impurities in Polar Ice: Artifacts or Not?

A series of experiments was undertaken to determine the origin of filaments found in grain boundaries and impurity spots found in grain interiors of polar ice during observation in the scanning electron microscope. It is shown that although the filaments are artifacts, they demonstrate the presence of impurities segregated to the grain boundary planes. It is also demonstrated that the impurities observed in the grain interior reside there and were not transported from the grain boundaries during specimen preparation or observation

Deliberate clinical inertia: Using meta-cognition to improve decision-making

Deliberate clinical inertia is the art of doing nothing as a positive response. To be able to apply this concept, individual clinicians need to specifically focus on their clinical decision-making. The skill of solving problems and making optimal clinical decisions requires more attention in medical training and should play a more prominent part of the medical curriculum. This paper provides suggestions on how this may be achieved. Strategies to mitigate common biases are outlined, with an emphasis on reversing a 'more is better' culture towards more temperate, critical thinking. To incorporate such an approach in medical curricula and in clinical practice, institutional endorsement and support is required

Extracellular oxidative metabolism of wood decay fungi

Substantial progress has been made toward understanding the fundamental physiology and genetics of wood decay fungi, microbes that are capable of degrading all major components of plant cell walls. Efficient utilization of lignocellulosic biomass has been hampered in part by limitations in our understanding of enzymatic mechanisms of plant cell wall degradation. This is particularly true of woody substrates where accessibility and high lignin content substantially complicate enzymatic 'deconstruction'. The interdisciplinary research has illuminated enzymatic mechanisms essential for the conversion of lignocellulosics to simple carbohydrates and other small molecular weight products. Progress was in large part dependent on substantial collaborations with the Department of Energy's Joint Genome Institute (JGI) in Walnut Creek and Los Alamos, as well as the Catholic University, Santiago, Chile, the Royal Institute of Technology, Stockholm, the University of Minnesota, St. Paul, and colleagues at the University of Wisconsin and the Forest Products Laboratory. Early accomplishments focused on the development of experimental tools (2, 7, 22, 24-26, 32) and characterization of individual genes and enzymes (1, 3-5, 8, 9, 11, 14, 15, 17, 18, 23, 27, 33). In 2004, the genome of the most intensively studied lignin-degrading fungus, Phanerochaete chrysosporium, was published (21). This milestone lead to additional progress on this important model system (6, 10, 12, 13, 16, 28-31) and was further complemented by genome analysis of other important cellulose-degrading fungi (19, 20). These accomplishments have been highly cited and have paved the way for whole new research areas

Extracellular oxidative metabolism of wood decay fungi

Substantial progress has been made toward understanding the fundamental physiology and genetics of wood decay fungi, microbes that are capable of degrading all major components of plant cell walls. Efficient utilization of lignocellulosic biomass has been hampered in part by limitations in our understanding of enzymatic mechanisms of plant cell wall degradation. This is particularly true of woody substrates where accessibility and high lignin content substantially complicate enzymatic 'deconstruction'. The interdisciplinary research has illuminated enzymatic mechanisms essential for the conversion of lignocellulosics to simple carbohydrates and other small molecular weight products. Progress was in large part dependent on substantial collaborations with the Department of Energy's Joint Genome Institute (JGI) in Walnut Creek and Los Alamos, as well as the Catholic University, Santiago, Chile, the Royal Institute of Technology, Stockholm, the University of Minnesota, St. Paul, and colleagues at the University of Wisconsin and the Forest Products Laboratory. Early accomplishments focused on the development of experimental tools (2, 7, 22, 24-26, 32) and characterization of individual genes and enzymes (1, 3-5, 8, 9, 11, 14, 15, 17, 18, 23, 27, 33). In 2004, the genome of the most intensively studied lignin-degrading fungus, Phanerochaete chrysosporium, was published (21). This milestone lead to additional progress on this important model system (6, 10, 12, 13, 16, 28-31) and was further complemented by genome analysis of other important cellulose-degrading fungi (19, 20). These accomplishments have been highly cited and have paved the way for whole new research areas

We are still largely in the dark as to whether incarceration reduces recidivism

One of the aims of prison is to reduce recidivism. Daniel P. Mears, Joshua C. Cochran, and Francis T. Cullen find, however, that research tells us little about the effects of prison on offending. They argue that if we want more effective punishment policy, we need better research on the conditions under which incarceration reduces recidivism or achieves other goals

Incident Ischemic Heart Disease After Long-Term Occupational Exposure to Fine Particulate Matter: Accounting for 2 Forms of Survivor Bias.

Little is known about the heart disease risks associated with occupational, rather than traffic-related, exposure to particulate matter with aerodynamic diameter of 2.5 µm or less (PM2.5). We examined long-term exposure to PM2.5 in cohorts of aluminum smelters and fabrication workers in the United States who were followed for incident ischemic heart disease from 1998 to 2012, and we addressed 2 forms of survivor bias. Left truncation bias was addressed by restricting analyses to the subcohort hired after the start of follow up. Healthy worker survivor bias, which is characterized by time-varying confounding that is affected by prior exposure, was documented only in the smelters and required the use of marginal structural Cox models. When comparing always-exposed participants above the 10th percentile of annual exposure with those below, the hazard ratios were 1.67 (95% confidence interval (CI): 1.11, 2.52) and 3.95 (95% CI: 0.87, 18.00) in the full and restricted subcohorts of smelter workers, respectively. In the fabrication stratum, hazard ratios based on conditional Cox models were 0.98 (95% CI: 0.94, 1.02) and 1.17 (95% CI: 1.00, 1.37) per 1 mg/m(3)-year in the full and restricted subcohorts, respectively. Long-term exposure to occupational PM2.5 was associated with a higher risk of ischemic heart disease among aluminum manufacturing workers, particularly in smelters, after adjustment for survivor bias

Natural Populations of Woodchuck Hepatitis Virus Contain Variant Precore and Core Sequences Including a Premature Stop Codon in the Epsilon Motif

We have determined a consensus sequence and the type and the frequency of spontaneous sequence variations in the woodchuck hepatitis virus (WHV) precore gene and the 5' region of the core gene in 101 serum samples from 53 naturally WHV-infected woodchucks by polymerase chain reaction sequencing. Twenty of the 53 woodchucks were found to have variant sequences. Ten patterns of variant sequences were identified in these 20 animals. WHV sequences from 4 woodchucks had 1 nucleotide change, 3 had 2 nucleotide changes and 3 had 3 nucleotide changes. The nucleotide changes were not randomly distributed, but were limited to only 8 sites. Four sites were in the epsilon motif of the precore gene and four were in the 5' region of the core gene. Sixteen of the 53 (30%) woodchucks had precore sequence variants. All altered sites were analogous to previously described mutations in hepatitis B virus. There was a nucleotide change at nucleotide 2016 in codon 29 of the precore region that produced a stop codon in 4 animals. This site is analogous to a common hepatitis B virus e antigen mutation. The sequence from the initial blood samples from 3 of 4 animals with this stop codon producing variant appeared to be the consensus sequence; however, in later samples the variant occurred as a mixed infection with the consensus sequence. The mixed infections were chronic and the proportion of the variant sequence was maintained or increased in the course of infection. In the fourth animal only the variant was found and it persisted for over 14 months of infection. WHV appears to be a valuable model for the study of the structure and function of the hepadnavirus precore region