Supplementary Table S1 from Loss of prostaglandin D2 synthase: a key molecular event in the transition of a low-grade astrocytoma to an anaplastic astrocytoma

Tuberculosis remains one of the most significant bacterial diseases globally and is exacerbated by a growing problem with antibiotic drug resistance. To control the spread of such resistance, it is important for public health authorities to know whether drug-resistant strains in their population have arisen from the ineffective treatment of a previously drug-sensitive case or from the transmission of already existing resistant cases. Data from outbreaks of tuberculosis frequently includes for each isolate, both genotypic information from a molecular marker and information about its drug resistance status. These data can be highly structured due to information about the evolution of the molecular marker, as well as the acquisition of drug resistance. In this chapter, we use this information to estimate key parameters related to drug resistance, such as the proportion of drug-resistant cases arising as a result of treatment failure or transmission.

ObjectiveAndrogen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance, and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high-affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein A (PAPP-A) - stanniocalcin 2 (STC2) axis. Design and methodsIn a blinded, randomised, cross-over design, 15 patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs was assessed. ResultsMetformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (P < 0.05) and IGFBP-3 (P < 0.01) but increased IGF bioactivity (P < 0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r(2)= 0.28, P < 0.05). PAPP-A remained unchanged but STC2 declined significantly (P < 0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r(2)= 0.35, P < 0.05). ConclusionMetformin administration alters many components of the circulating IGF system, either directly or indirectly via improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.

Background As oesophageal cancer has short survival, it is likely pre-diagnosis health behaviours will have carry-over effects on post-diagnosis survival times. Cancer registry data sets do not usually contain pre-diagnosis health behaviours and so need to be augmented with data from external health surveys. A new algorithm is introduced and tested to augment cancer registries with external data when one-to-one data linkage is not available. Methods The algorithm is to use external health survey data to impute pre-diagnosis health behaviour for cancer patients, estimate misclassification errors in these imputed values and then fit misclassification corrected Cox regression to quantify the association between pre-diagnosis health behaviour and post-diagnosis survival. Data from US cancer registries and a US national health survey are used in testing the algorithm. Results It is demonstrated that the algorithm works effectively on simulated smoking data when there is no age confounding. But age confounding does exist (risk of death increases with age and most health behaviours change with age) and interferes with the performance of the algorithm. The estimate of the hazard ratio (HR) of pre-diagnosis smoking was HR = 1.32 (95% CI 0.82,2.68) with HR = 1.93 (95% CI 1.08,7.07) in the squamous cell sub-group and pre-diagnosis physical activity was protective of survival with HR = 0.25 (95% CI 0.03, 0.81). But the method failed for less common behaviours (such as heavy drinking). Conclusions Further improvements in the I2C2 algorithm will permit enrichment of cancer registry data through imputation of new variables with negligible risk to patient confidentiality, opening new research opportunities in cancer epidemiology.

Background For epidemiological research, cancer registry datasets often need to be augmented with additional data. Data linkage is not feasible when there are no cases in common between data sets. We present a novel approach to augmenting cancer registry data by imputing pre-diagnosis health behaviour and estimating its relationship with post-diagnosis survival time. Methods Six measures of pre-diagnosis health behaviours (focussing on tobacco smoking, 'at risk' alcohol consumption, overweight and exercise) were imputed for 28,000 cancer registry data records of US oesophageal cancers using cold deck imputation from an unrelated health behaviour dataset. Each data point was imputed twice. This calibration allowed us to estimate the misclassification rate. We applied statistical correction for the misclassification to estimate the relative risk of dying within 1 year of diagnosis for each of the imputed behaviour variables. Subgroup analyses were conducted for adenocarcinoma and squamous cell carcinoma separately. Results Simulated survival data confirmed that accurate estimates of true relative risks could be retrieved for health behaviours with greater than 5% prevalence, although confidence intervals were wide. Applied to real datasets, the estimated relative risks were largely consistent with current knowledge. For example, tobacco smoking status 5 years prior to diagnosis was associated with an increased age-adjusted risk of all cause death within 1 year of diagnosis for oesophageal squamous cell carcinoma (RR = 1.99 95% CI 1.24,3.12) but not oesophageal adenocarcinoma RR = 1.61, 95% CI 0.79,2.57). Conclusions We have demonstrated a novel imputation-based algorithm for augmenting cancer registry data for epidemiological research which can be used when there are no cases in common between data sets. The algorithm allows investigation of research questions which could not be addressed through direct data linkage.

Background Information on the associations between pre-diagnosis health behavior and post-diagnosis survival time in esophageal cancer could assist in planning health services but can be difficult to obtain using established study designs. We postulated that, with a large data set, using estimated probability for a behavior as a predictor of survival times could provide useful insight as to the impact of actual behavior. Methods Data from a national health survey and logistic regression were used to calculate the probability of selected health behaviors from participant’s demographic characteristics for each esophageal cancer case within a large cancer registry data base. The associations between survival time and the probability of the health behaviors were investigated using Cox regression. Results Observed associations include: a 0.1 increase in the probability of smoking 1 year prior to diagnosis was detrimental to survival (Hazard Ratio (HR) 1.21, 95% CI 1.19,1.23); a 0.1 increase in the probability of hazardous alcohol consumption 10 years prior to diagnosis was associated with decreased survival in squamous cell cancer (HR 1.29, 95% CI 1.07, 1.56) but not adenocarcinoma (HR 1.08, 95% CI 0.94,1.25); a 0.1 increase in the probability of physical activity outside the workplace is protective (HR 0.83, 95% CI 0.81,0.84). Conclusions We conclude that probability for health behavior estimated from demographic characteristics can provide an initial assessment of the association between pre-diagnosis health behavior and post-diagnosis health outcomes, allowing some sharing of information across otherwise unrelated data collections.

Introduction Androgen deprivation therapy (ADT) has detrimental effects on body composition, metabolic health, physical functioning, bone mineral density (BMD) and health-related quality of life (HRQOL) in men with prostate cancer. We investigated whether a 12-month home-based progressive resistance training (PRT) programme, instituted at the start of ADT, could prevent these adverse effects. Methods Twenty-five patients scheduled to receive at least 12 months of ADT were randomly assigned to either usual care (UC) ( n = 12) or PRT ( n = 13) starting immediately after their first ADT injection. Body composition, body cell mass (BCM; a functional component of lean body mass), BMD, physical function, insulin sensitivity and HRQOL were measured at 6 weeks and 6 and 12 months. Data were analysed by a linear mixed model. Results ADT had a negative impact on body composition, BMD, physical function, glucose metabolism and HRQOL. At 12 months, the PRT group had greater reductions in BCM by − 1.9 ± 0.8 % ( p = 0.02) and higher gains in fat mass by 3.1 ± 1.0 % ( p = 0.002), compared to the UC group. HRQOL domains were maintained or improved in the PRT versus UC group at 6 weeks (general health, p = 0.04), 6 months (vitality, p = 0.02; social functioning, p = 0.03) and 12 months (mental health, p = 0.01; vitality, p = 0.02). A significant increase in the Matsuda Index in the PRT versus UC group was noted at 6 weeks ( p = 0.009) but this difference was not maintained at subsequent timepoints. Between-group differences favouring the PRT group were also noted for physical activity levels (step count) ( p = 0.02). No differences in measures of BMD or physical function were detected at any time point. Conclusion A home-based PRT programme instituted at the start of ADT may counteract detrimental changes in body composition, improve physical activity and mental health over 12 months. Trial registration Australian and New Zealand Clinical Trials Registry, ACTRN12616001311448

Background: Information on the associations between pre-diagnosis health behavior and post-diagnosis survival time in esophageal cancer could assist in choosing treatments and planning health services but can be difficult to obtain using established study designs. We postulated that, with a large data set, using estimated propensity for a behavior as a predictor of survival times could provide useful insight as to the impact of actual behavior. Methods: Data from a national health survey and logistic regression were used to calculate the propensity of selected health behaviors from participant’s demographic characteristics for each esophageal cancer case within a large cancer registry data base. The associations between survival time and the propensity of the health behaviors were investigated using Cox regression. Results: Observed associations include: a 0.1 increase in the probability of smoking one year prior to diagnosis was detrimental to survival (Hazard Ratio (HR) 1.21, 95% CI 1.19,1.23); a 0.1 increase in the probability of hazardous alcohol consumption 10 years prior to diagnosis was associated with decreased survival in squamous cell cancer (HR 1.29, 95% CI 1.07, 1.56) but not adenocarcinoma (HR 1.08, 95% CI 0.94,1.25); a 0.1 increase in the probability of physical activity outside the workplace is protective (HR 0.83, 95% CI 0.81,0.84). Conclusions: We conclude that propensity for health behavior estimated from demographic characteristics can assist in determining existence of the association between pre-diagnosis health behavior and post-diagnosis health outcomes, allowing some sharing information across otherwise unrelated data collections.

ContextAndrogen deprivation therapy (ADT) in prostate cancer results in muscular atrophy, due to loss of the anabolic actions of testosterone. Recently, we discovered that testosterone acts on the hepatic urea cycle to reduce amino acid nitrogen elimination. We now hypothesize that ADT enhances protein oxidative losses by increasing hepatic urea production, resulting in muscle catabolism. We also investigated whether progressive resistance training (PRT) can offset ADT-induced changes in protein metabolism.ObjectiveTo investigate the effect of ADT on whole-body protein metabolism and hepatic urea production with and without a home-based PRT program.DesignA randomized controlled trial.Patients and interventionTwenty-four prostate cancer patients were studied before and after 6 weeks of ADT. Patients were randomized into either usual care (UC) (n = 11) or PRT (n = 13) starting immediately after ADT.Main outcome measuresThe rate of hepatic urea production was measured by the urea turnover technique using15N2-urea. Whole-body leucine turnover was measured, and leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, was calculated.ResultsADT resulted in a significant mean increase in hepatic urea production (from 427.6 ± 18.8 to 486.5 ± 21.3;P < 0.01) regardless of the exercise intervention. Net protein loss, as measured by Lox/Lra, increased by 12.6 ± 4.9% (P < 0.05). PRT preserved lean body mass without affecting hepatic urea production.ConclusionAs early as 6 weeks after initiation of ADT, the suppression of testosterone increases protein loss through elevated hepatic urea production. Short-term PRT was unable to offset changes in protein metabolism during a state of profound testosterone deficiency.

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There have been a significant number of recent papers about hyperspectral imaging, which propose various methods for estimating the number of materials/endmembers in hyperspectral images. This is sometimes called the “intrinsic” dimension (ID) of the image. Estimation of the error variance in each spectral band is a critical first step in ID estimation. The estimated error variances can then be used to preprocess (e.g., whiten) the data, prior to ID estimation. A range of variance estimation methods have been advocated in the literature. We investigate the impact of five variance estimation methods (three using spatial information and two using spectral information) on five ID estimation methods, with the aid of four different, but semirealistic, sets of simulated hyperspectral images. Our findings are as follows: first, for all four sets, the two spectral variance estimation methods significantly outperform the three spatial methods; second, when used with the spectral variance estimation methods, two of the ID estimation methods (called random matrix theory and NWHFC) consistently outperform the other three ID estimation methods; third, the better spectral variance estimation method sometimes gives negative variance estimates; fourth, we introduce a simple correction that guarantees positivity; and fifth, we give a fast algorithm for its computation.

CONTEXTGrowth hormone (GH) stimulates connective tissue and muscle growth, an effect that is potentiated by testosterone. Decorin, a myokine and a connective tissue protein, stimulates connective tissue accretion and muscle hypertrophy. Whether GH and testosterone regulate decorin in humans is not known.OBJECTIVETo determine whether decorin is stimulated by GH and testosterone.DESIGNRandomized, placebo-controlled, double-blind study.PARTICIPANTS AND INTERVENTION96 recreationally trained athletes (63 men, 33 women) received 8 weeks of treatment followed by a 6-week washout period. Men received placebo, GH (2 mg/day), testosterone (250 mg/week) or combination. Women received either placebo or GH (2 mg/day).MAIN OUTCOME MEASURESerum decorin concentration.RESULTSGH treatment significantly increased mean serum decorin concentration by 12.7 ± 4.2%; P < 0.01. There was a gender difference in the decorin response to GH, with greater increase in men than in women (∆ 16.5 ± 5.3%; P < 0.05 compared to ∆ 9.4 ± 6.5%; P = 0.16). Testosterone did not significantly change serum decorin. Combined GH and testosterone treatment increased mean decorin concentration by 19.5 ± 3.7% (P < 0.05), a change not significantly different from GH alone.CONCLUSIONGH significantly increases circulating decorin, an effect greater in men than in women. Decorin is not affected by testosterone. We conclude that GH positively regulates decorin in humans in a gender-dimorphic manner.

Automatic hashtag segmentation is used when analysing twitter data, to associate hashtag terms to those used in common language. The most common form of hashtag segmentation uses a dictionary with a probability distribution over the dictionary terms, constructed from sample texts specific to the given hashtag domain. The language used in Twitter is different to the common language found in published literature, most likely due to the tweet character limit, therefore dictionaries constructed to perform hashtag segmentation should be derived from a random sample of tweets. We ask the question "How large should our sample of tweets be to obtain a given level of segmentation accuracy?" We found that the Jaccard similarity between the correct segmentation and the predicted segmentation using a unigram model, follows a Zero-One inflated Beta distribution with four parameters. We also found that each of these four parameters are functions of the sample size (tweet count) for dictionary construction, implying that we can compute the Jaccard similarity distribution once the tweet count of the dictionary is known. Having this model allows us to compute the number of tweets required for a given level of hashtag segmentation accuracy, and also allows us to compare other segmentation models to this known distribution.

AbstractSeeds of some eastern Australian Grevillea species show the characteristics of non-deep physiological dormancy, which is broken by exposure to heat shock and/or smoke. The current study tested whether the restrictive effect of the seed coat on germination was localized to specific regions, whether the fire cues affected the growth potential of the embryo, the mechanical strength of the seed coat itself, and the anatomy of fracturing of the seed coat. Removal of the micropylar seed coat allowed germination, while retaining it in place restricted germination. The growth potential of the embryo was increased by exposure to heat shock or to smoke, and increased the most if exposed to both cues. Estimation of the minimum force required by embryos to germinate from intact seeds suggested that this force was reduced for seeds treated with fire cues. The fire cues did not affect the resistance of the seed coat to compressive force when tested after 24 h of imbibition. Fracturing of the seed coat occurred between cell walls, except for the palisade layer, where fracturing occurred across palisade and sclerenchyma cells. While the micropylar end of the seed coat imposes dormancy, most likely by mechanical constraint, heat shock and smoke overcome dormancy by increasing the embryo's growth potential and possibly weakening the seed coat, either directly or via the embryo.