Using Markov chain Monte Carlo methods for estimating parameters with gravitational radiation data

We present a Bayesian approach to the problem of determining parameters for coalescing binary systems observed with laser interferometric detectors. By applying a Markov Chain Monte Carlo (MCMC) algorithm, specifically the Gibbs sampler, we demonstrate the potential that MCMC techniques may hold for the computation of posterior distributions of parameters of the binary system that created the gravity radiation signal. We describe the use of the Gibbs sampler method, and present examples whereby signals are detected and analyzed from within noisy data.Comment: 21 pages, 10 figure

A refined risk stratification scheme for clinical stage 1 NSGCT based on evaluation of both embryonal predominance and lymphovascular invasion

Background: Active surveillance is an increasingly accepted approach for managing patients with germ-cell tumors (GCTs) after an orchiectomy. Here we investigate a time-to-relapse stratification scheme for clinical stage 1 (CS1) nonseminoma GCT (NSGCT) patients according to factors associated with relapse and identify a group of patients with a lower frequency and longer time-to-relapse who may require an alternative surveillance strategy. Patients and methods: We analyzed 266 CS1 GCT patients from the IRB-approved DFCI GCT database that exclusively underwent surveillance following orchiectomy from 1997 to 2013. We stratified NSGCT patients according to predominance of embryonal carcinoma (EmbP) and lymphovascular invasion (LVI), using a 0, 1, and 2 scoring system. Cox regression and conditional risk analysis were used to compare each NSGCT group to patients in the seminomatous germ-cell tumor (SGCT) category. Median time-to-relapse values were then calculated among those patients who underwent relapse. Relapse-free survival curves were generated using the Kaplan–Meier method. Results: Fifty (37%) NSGCT and 20 (15%) SGCT patients relapsed. The median time-to-relapse was 11.5 versus 6.3 months for the SGCT and NSGCT groups, respectively. For NSGCT patients, relapse rates were higher and median timeto- relapse faster with increasing number of risk factors (RFs). Relapse rates (%) and median time-to-relapse (months) were 25%/8.5 months, 41%/6.8 months and 78%/3.8 months for RF0, RF1 and RF2, respectively. We found a statistically significant difference between SGCT and patients with one or two RFs (P < 0.001) but not between SGCT and NSGCT RF0 (P = 0.108). Conclusion: NSGCT patients grouped by a risk score system based on EmbP and LVI yielded three groups with distinct relapse patterns -and patients with neither EmbP nor LVI appear to behave similar to SGCT.C. A. Lago-Hernandez, H. Feldman, E. O, Donnell, B. A. Mahal, V. Perez, S. Howard, M. Rosenthal, S. C. Cheng, P. L. Nguyen, C. Beard, A. V. D, Amico, C. J. Sweene

Persistent elevation of urine aquaporin-2 during water loading in a child with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) caused by a R137L mutation in the V2 vasopressin receptor

Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) is a novel disease caused by a gain-of-function mutation in the V2 vasopressin receptor (V2R), which results in water overload and hyponatremia. We report the effect of water loading in a 3-year old boy with NSIAD, diagnosed in infancy, to assess urine aquaporin-2 (AQP2) excretion as a marker for V2R activation, and to evaluate the progression of the disease since diagnosis. The patient is one of the first known NSIAD patients and the only patient with a R137L mutation. Patient underwent a standard water loading test in which serum and urine sodium and osmolality, serum AVP, and urine AQP2 excretion were measured. The patient was also evaluated for ad lib fluid intake before and after the test. This patient demonstrated persistent inability to excrete free water. Only 39% of the water load (20 ml/kg) was excreted during a 4-hour period (normal ≥ 80-90%). Concurrently, the patient developed hyponatremia and serum hypoosmolality. Serum AVP levels were detectable at baseline and decreased one hour after water loading; however, urine AQP2 levels were elevated and did not suppress normally during the water load. The patient remained eunatremic but relatively hypodipsic during ad lib intake. In conclusion, this is the first demonstration in a patient with NSIAD caused by a R137L mutation in the V2R that urine AQP2 excretion is inappropriately elevated and does not suppress normally with water loading. In addition, this is the first longitudinal report of a pediatric patient with NSIAD diagnosed in infancy who demonstrates the ability to maintain eunatremia during ad lib dietary intake

'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

The Isolation of Nucleic Acids from Fixed, Paraffin-Embedded Tissues–Which Methods Are Useful When?

Museums and pathology collections around the world represent an archive of genetic material to study populations and diseases. For preservation purposes, a large portion of these collections has been fixed in formalin-containing solutions, a treatment that results in cross-linking of biomolecules. Cross-linking not only complicates isolation of nucleic acid but also introduces polymerase “blocks” during PCR. A wide variety of methods exists for the recovery of DNA and RNA from archival tissues, and although a number of previous studies have qualitatively compared the relative merits of the different techniques, very few have undertaken wide scale quantitative comparisons. To help address this issue, we have undertaken a study that investigates the quality of nucleic acids recovered from a test panel of fixed specimens that have been manipulated following a number of the published protocols. These include methods of pre-treating the samples prior to extraction, extraction and nucleic acid purification methods themselves, and a post-extraction enzymatic repair technique. We find that although many of the published methods have distinct positive effects on some characteristics of the nucleic acids, the benefits often come at a cost. In addition, a number of the previously published techniques appear to have no effect at all. Our findings recommend that the extraction methodology adopted should be chosen carefully. Here we provide a quick reference table that can be used to determine appropriate protocols for particular aims

Assessing the Effects of Personal Characteristics and Context on U.S. House Speakers’ Leadership Styles, 1789-2006

Research on congressional leadership has been dominated in recent decades by contextual interpretations that see leaders’ behavior as best explained by the environment in which they seek to exercise leadership—particularly, the preference homogeneity and size of their party caucus. The role of agency is thus discounted, and leaders’ personal characteristics and leadership styles are underplayed. Focusing specifically on the speakers of the U.S. House of Representatives from the first to the 110th Congress, we construct measures of each speaker’s commitment to comity and leadership assertiveness. We find the scores reliable and then test the extent to which a speaker’s style is the product of both political context and personal characteristics. Regression estimates on speakers’ personal assertiveness scores provide robust support for a context-plus-personal characteristics explanation, whereas estimates of their comity scores show that speakers’ personal backgrounds trump context

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts