A simple method for assigning genomic grade to individual breast tumours

<p>Abstract</p> <p>Background</p> <p>The prognostic value of grading in breast cancer can be increased with microarray technology, but proposed strategies are disadvantaged by the use of specific training data or parallel microscopic grading. Here, we investigate the performance of a method that uses no information outside the breast profile of interest.</p> <p>Results</p> <p>In 251 profiled tumours we optimised a method that achieves grading by comparing rank means for genes predictive of high and low grade biology; a simpler method that allows for truly independent estimation of accuracy. Validation was carried out in 594 patients derived from several independent data sets. We found that accuracy was good: for low grade (G1) tumors 83- 94%, for high grade (G3) tumors 74- 100%. In keeping with aim of improved grading, two groups of intermediate grade (G2) cancers with significantly different outcome could be discriminated.</p> <p>Conclusion</p> <p>This validates the concept of microarray-based grading in breast cancer, and provides a more practical method to achieve it. A simple R script for grading is available in an additional file. Clinical implementation could achieve better estimation of recurrence risk for 40 to 50% of breast cancer patients.</p

Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in the Detection of Clinically Significant Prostate Cancer in the Prostate Imaging Reporting and Data System Era: A Systematic Review and Meta-analysis

CONTEXT: Prebiopsy multiparametric magnetic resonance imaging (mpMRI) is increasingly used in prostate cancer diagnosis. The reported negative predictive value (NPV) of mpMRI is used by some clinicians to aid in decision making about whether or not to proceed to biopsy. OBJECTIVE: We aim to perform a contemporary systematic review that reflects the latest literature on optimal mpMRI techniques and scoring systems to update the NPV of mpMRI for clinically significant prostate cancer (csPCa). EVIDENCE ACQUISITION: We conducted a systematic literature search and included studies from 2016 to September 4, 2019, which assessed the NPV of mpMRI for csPCa, using biopsy or clinical follow-up as the reference standard. To ensure that studies included in this analysis reflect contemporary practice, we only included studies in which mpMRI findings were interpreted according to the Prostate Imaging Reporting and Data System (PIRADS) or similar Likert grading system. We define negative mpMRI as either (1) PIRADS/Likert 1-2 or (2) PIRADS/Likert 1-3; csPCa was defined as either (1) Gleason grade group ≥2 or (2) Gleason grade group ≥3. We calculated NPV separately for each combination of negative mpMRI and csPCa. EVIDENCE SYNTHESIS: A total of 42 studies with 7321 patients met our inclusion criteria and were included for analysis. Using definition (1) for negative mpMRI and csPCa, the pooled NPV for biopsy-naïve men was 90.8% (95% confidence interval [CI] 88.1-93.1%). When defining csPCa using definition (2), the NPV for csPCa was 97.1% (95% CI 94.9-98.7%). Calculation of the pooled NPV using definition (2) for negative mpMRI and definition (1) for csPCa yielded the following: 86.8% (95% CI 80.1-92.4%). Using definition (2) for both negative mpMRI and csPCa, the pooled NPV from two studies was 96.1% (95% CI 93.4-98.2%). CONCLUSIONS: Multiparametric MRI of the prostate is generally an accurate test for ruling out csPCa. However, we observed heterogeneity in the NPV estimates, and local institutional data should form the basis of decision making if available. PATIENT SUMMARY: The negative predictive values should assist in decision making for clinicians considering not proceeding to biopsy in men with elevated age-specific prostate-specific antigen and multiparametric magnetic resonance imaging reported as negative (or equivocal) on Prostate Imaging Reporting and Data System/Likert scoring. Some 7-10% of men, depending on the setting, will miss a diagnosis of clinically significant cancer if they do not proceed to biopsy. Given the institutional variation in results, it is of upmost importance to base decision making on local data if available

Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients

BACKGROUND: Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization. METHODS: We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes – basal-like, ERBB2, luminal A/B and normal-like – and characterized these subtypes extensively with the use of conventional clinical variables. RESULTS: We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders. CONCLUSION: We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability

Galaxies and Cladistics

The Hubble tuning fork diagram, based on morphology and established in the 1930s, has always been the preferred scheme for classification of galaxies. However, the current large amount of multiwavelength data, most often spectra, for objects up to very high distances, asks for more sophisticated statistical approaches. Interpreting formation and evolution of galaxies as a ?transmission with modification' process, we have shown that the concepts and tools of phylogenetic systematics can be heuristically transposed to the case of galaxies. This approach, which we call ?astrocladistics', has successfully been applied on several samples. Many difficulties still remain, some of them being specific to the nature of both galaxies and their diversification processes, some others being classical in cladistics, like the pertinence of the descriptors in conveying any useful evolutionary information.Comment: Talk given at the "12th Evolutionary Biology Meeting" held in Marseille, France, Sept. 24-26, 200

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

Timing of Subsequent Fractures after an Initial Fracture

A prior fracture is a well-documented risk factor for a subsequent fracture and it doubles the risk of subsequent fractures. Few studies have investigated the time that elapses between the initial and subsequent fracture. These studies show that the subsequent fracture risk is not constant, but fluctuates over time. The risk of subsequent vertebral, hip, and nonvertebral non-hip fractures is highest immediately after initial hip, clinical, and radiographic vertebral fractures and nonvertebral fractures and declines afterward, regardless of gender, age, and initial fracture location. These studies indicate the need for early action after an initial fracture with medical interventions that have an effect within a short term to reduce the preventable risks of subsequent fractures

Secular Evolution and the Growth of Pseudobulges in Disk Galaxies

Galaxy evolution is in transition from an early universe dominated by hierarchical clustering to a future dominated by secular processes. These result from interactions involving collective phenomena such as bars, oval disks, spiral structure, and triaxial dark halos. This paper summarizes a review by Kormendy & Kennicutt (2004) using, in part, illustrations of different galaxies. In simulations, bars rearrange disk gas into outer rings, inner rings, and galactic centers, where high gas densities feed starbursts. Consistent with this picture, many barred and oval galaxies have dense central concentrations of gas and star formation rates that can build bulge-like stellar densities on timescales of a few billion years. We conclude that secular evolution builds dense central components in disk galaxies that look like classical, merger-built bulges but that were made slowly out of disk gas. We call these pseudobulges. Many pseudobulges can be recognized because they have characteristics of disks: (1) flatter shapes than those of classical bulges, (2) correspondingly large ratios of ordered to random velocities, (3) small velocity dispersions, (4) spiral structure or nuclear bars, (5) nearly exponential brightness profiles, and (6) starbursts. These structures occur preferentially in barred and oval galaxies in which secular evolution should be most rapid. Thus a variety of observational and theoretical results contribute to a new paradigm of secular evolution that complements hierarchical clustering.Comment: 19 pages, 9 Postscript figures; requires kapproc.cls and procps.sty; to appear in "Penetrating Bars Through Masks of Cosmic Dust: The Hubble Tuning Fork Strikes a New Note", ed. Block, Freeman, Puerari, Groess, and Block, Dordrecht: Kluwer, in press; for a version with full resolution figures, see http://chandra.as.utexas.edu/~kormendy/ar3ss.htm

Cardiorespiratory and perceptual responses to self-regulated and imposed submaximal arm-leg ergometry

Purpose: This study compared cardiorespiratory and perceptual responses to exercise using self-regulated and imposed power outputs distributed between the arms and legs. Methods Ten males (age 21.7 ± 3.4 years) initially undertook incremental arm-crank ergometry (ACE) and cycle ergometry (CYC) tests to volitional exhaustion to determine peak power output (Wpeak). Two subsequent tests involved 20-min combined arm–leg ergometry (ALE) trials, using imposed and self-regulated protocols, both of which aimed to elicit an exercising heart rate of 160 beats min−1. During the imposed trial, arm and leg intensity were set at 40% of each ergometer-specific Wpeak. During the self-regulated trial, participants were asked to self-regulate cadence and resistance to achieve the target heart rate. Heart rate (HR), oxygen uptake (V˙O2 ), pulmonary ventilation (V˙E ), and ratings of perceived exertion (RPE) were recorded continuously. Results As expected, there were no differences between imposed and self-regulated trials for HR, V˙O2 , and V˙E (all P ≥ 0.05). However, central RPE and local RPE for the arms were lower during self-regulated compared imposed trials (P ≤ 0.05). Lower RPE during the self-regulated trial was related to preferential adjustments in how the arms (33 ± 5% Wpeak) and legs (46 ± 5% Wpeak) contributed to the exercise intensity. Conclusions: This study demonstrates that despite similar metabolic and cardiovascular strain elicited by imposed and self-regulated ALE, the latter was perceived to be less strenuous, which is related to participants doing more work with the legs and less work with the arms to achieve the target intensity

Quantifying Morphological Evolution from Low to High Redshifts

Establishing the morphological history of ordinary galaxies was one of the original goals for the Hubble Space Telescope, and remarkable progress toward achieving this this goal has been made. How much of this progress has been at the expense of the Hubble sequence? As we probe further out in redshift space, it seems time to re-examine the underlying significance of Hubble's tuning fork in light of the the spectacular and often bizarre morphological characteristics of high redshift galaxies. The aim of this review is to build a morphological bridge between high-redshift and low-redshift galaxy populations, by using quantitative morphological measures to determine the maximum redshift for which the Hubble sequence provides a meaningful description of the galaxy population. I will outline the various techniques used to quantify high-redshift galaxy morphology, highlight the aspects of the Hubble sequence being probed by these techniques, and indicate what is getting left behind. I will argue that at higher redshifts new techniques (and new ideas) that place less emphasis on classical morphology and more emphasis on the link between morphology and resolved stellar populations are needed in order to probe the evolutionary history of high-redshift galaxies

European integration assessed in the light of the 'rules vs. standards debate'

The interplay of various legal systems in the European Union (EU) has long triggered a debate on the tension between uniformity and diversity of Member States' (MS) laws. This debate takes place among European legal scholars and is also paralleled by economic scholars, e.g. in the ambit of the 'theory of federalism'. This paper takes an innovative perspective on the discrepancy between 'centralized' and 'decentralized' law-making in the EU by assessing it with the help of the rules versus standards debate. When should the EU legislator grant the national legislator leeway in the formulation of new laws and when should all be fixed ex ante at European level? The literature on the 'optimal shape of legal norms' shall be revisited in the light of law-making in the EU, centrally dealing with the question how much discretion shall be given to the national legislator; and under which circumstances. This paper enhances the established decisive factors for the choice of a rule or a standard in a national setting (complexity, volatility, judges' specialization and frequency of application) by two new crucial factors (switching costs and the benefit of uniformity in terms of information costs) in order to assess law-making policies at EU level