Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS).

BackgroundFor men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.MethodsUrine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).ResultsSeven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.ConclusionsPCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies

Validation of continuous clinical indices of cardiometabolic risk in a cohort of Australian adults

Background: Indicators of cardiometabolic risk typically include non-clinical factors (e.g., smoking). While the incorporation of non-clinical factors can improve absolute risk prediction, it is impossible to study the contribution of non-clinical factors when they are both predictors and part of the outcome measure. Metabolic syndrome, incorporating only clinical measures, seems a solution yet provides no information on risk severity. The aims of this study were: 1) to construct two continuous clinical indices of cardiometabolic risk (cCICRs), and assess their accuracy in predicting 10-year incident cardiovascular disease and/or type 2 diabetes; and 2) to compare the predictive accuracies of these cCICRs with existing risk indicators that incorporate non-clinical factors (Framingham Risk Scores). Methods: Data from a population-based biomedical cohort (n = 4056) were used to construct two cCICRs from waist circumference, mean arteriole pressure, fasting glucose, triglycerides and high density lipoprotein: 1) the mean of standardised risk factors (cCICR-Z); and 2) the weighted mean of the two first principal components from principal component analysis (cCICR-PCA). The predictive accuracies of the two cCICRs and the Framingham Risk Scores were assessed and compared using ROC curves. Results: Both cCICRs demonstrated moderate accuracy (AUCs 0.72 – 0.76) in predicting incident cardiovascular disease and/or type 2 diabetes, among men and women. There were no significant differences between the predictive accuracies of the cCICRs and the Framingham Risk Scores. Conclusions: cCICRs may be useful in research investigating associations between non-clinical factors and health by providing suitable alternatives to current risk indicators which include non-clinical factors.Suzanne J Carroll, Catherine Paquet, Natasha J Howard, Robert J Adams, Anne W Taylor and Mark Danie

Magnetic properties of Co2C and Co3C nanoparticles and their assemblies

Nano-composite material consisting of Co2C and Co3C nanoparticles has recently been shown to exhibit unusually large coercivities and energy products. Experimental studies that can delineate the properties of individual phases have been undertaken and provide information on how the coercivities and the energy product change with the size and composition of the nanoparticles. The studies indicate that while both phases are magnetic, the Co3C has higher magnetization and coercivity compared to Co2C. Through first principles electronic structure studies using a GGA+U functional, we provide insight on the role of C intercalation on enhancing the magnetic anisotropy of the individual phases

Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer.

The introduction of serum Prostate Specific Antigen (PSA) testing nearly 30 years ago has been associated with a significant shift towards localized disease and decreased deaths due to prostate cancer. Recognition that PSA testing has caused over diagnosis and over treatment of prostate cancer has generated considerable controversy over its value, and has spurred efforts to identify prognostic biomarkers to distinguish patients who need treatment from those that can be observed. Recent studies show that cancer is heterogeneous and forms a hierarchy of tumor cell populations. We developed a method of identifying prostate cancer differentiation states related to androgen signaling using Boolean logic. Using gene expression data, we identified two markers, CD38 and ARG2, that group prostate cancer into three differentiation states. Cancers with CD38-, ARG2- expression patterns, corresponding to an undifferentiated state, had significantly lower 10-year recurrence-free survival compared to the most differentiated group (CD38+ARG2+). We carried out immunohistochemical (IHC) staining for these two markers in a single institution (Stanford; n = 234) and multi-institution (Canary; n = 1326) cohorts. IHC staining for CD38 and ARG2 in the Stanford cohort demonstrated that combined expression of CD38 and ARG2 was prognostic. In the Canary cohort, low CD38 protein expression by IHC was significantly associated with recurrence-free survival (RFS), seminal vesicle invasion (SVI), extra-capsular extension (ECE) in univariable analysis. In multivariable analysis, ARG2 and CD38 IHC staining results were not independently associated with RFS, overall survival, or disease-specific survival after adjusting for other factors including SVI, ECE, Gleason score, pre-operative PSA, and surgical margins

Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.

Pediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation program, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberrant epigenetic program controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (MYC). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumor-suppressive activities in several other tumor types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives coordinated suppression of the MYC-driven core circuit supporting neuroblast identity and proliferation, while simultaneously activating an enduring gene program driving mitotic exit and neuronal differentiation. IMPLICATIONS: These findings indicate that targeting phosphorylation of ASCL1 may offer a new approach to development of differentiation therapies in neuroblastoma. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/12/1759/F1.large.jpg.Work was supported by Cancer Research UK Programme Grant RG91505 (AP), Wellcome Trust Investigator Award 212253/Z/18/Z (AP), MRC Research Grant MR/L021129/1 (F.A, A.P); Neuroblastoma UK (D.M, T.P, A.P), CRUK Cambridge Centre Paediatric Programme (L.P), The Terry Fox Foundation (FA), MBRU College of Medicine Internal grant award MBRU-CM-RG2019-14 (FA), MBRU-ALMAHMEED Collaborative Research Award ALM1909 (FA) and core support from the Wellcome Trust and the MRC Cambridge Stem Cell Institute (F.A, D.M, J.D., A.P.) and Cancer Research UK Cambridge Insititute (I.C, J.C)

U.S. Government engagement in support of global disease surveillance

Global cooperation is essential for coordinated planning and response to public health emergencies, as well as for building sufficient capacity around the world to detect, assess and respond to health events. The United States is committed to, and actively engaged in, supporting disease surveillance capacity building around the world. We recognize that there are many agencies involved in this effort, which can become confusing to partner countries and other public health entities. This paper aims to describe the agencies and offices working directly on global disease surveillance capacity building in order to clarify the United States Government interagency efforts in this space

On reminder effects, drop-outs and dominance: evidence from an online experiment on charitable giving

We present the results of an experiment that (a) shows the usefulness of screening out drop-outs and (b) tests whether different methods of payment and reminder intervals affect charitable giving. Following a lab session, participants could make online donations to charity for a total duration of three months. Our procedure justifying the exclusion of drop-outs consists in requiring participants to collect payments in person flexibly and as known in advance and as highlighted to them later. Our interpretation is that participants who failed to collect their positive payments under these circumstances are likely not to satisfy dominance. If we restrict the sample to subjects who did not drop out, but not otherwise, reminders significantly increase the overall amount of charitable giving. We also find that weekly reminders are no more effective than monthly reminders in increasing charitable giving, and that, in our three months duration experiment, standing orders do not increase giving relative to one-off donations

The OECD and phases in the international political economy, 1961–2011

In 2011, the OECD turned fifty. To provide a broad foundation for further thinking on this organization, we analyse its evolution over half a century from two perspectives: phases in the international political economy and the literature on IPE. By so doing, we uncover two paradoxes. Firstly, we find that the organization’s evolution closely mirrored major phases in the postwar international political economy until recently. However, the OECD’s long-term dependence on theWest has now become an obstacle to its efforts to adapt to the latest phase, characterised by the rise of non-Western powers. Secondly, we show that, during the OECD’s “golden age”, scholars paid relatively little attention to the organization but, from the 2000s, as the organization faced an unprecedented challenge of its potential economic decline, IPE literature on the organization blossomed