BRAF mutation is not predictive of long-term outcome in papillary thyroid carcinoma

The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1–2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1–2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1–2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan–Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy

Postnatal Survival of Mice with Maternal Duplication of Distal Chromosome 7 Induced by a Igf2/H19 Imprinting Control Region Lacking Insulator Function

The misexpressed imprinted genes causing developmental failure of mouse parthenogenones are poorly defined. To obtain further insight, we investigated misexpressions that could cause the pronounced growth deficiency and death of fetuses with maternal duplication of distal chromosome (Chr) 7 (MatDup.dist7). Their small size could involve inactivity of Igf2, encoding a growth factor, with some contribution by over-expression of Cdkn1c, encoding a negative growth regulator. Mice lacking Igf2 expression are usually viable, and MatDup.dist7 death has been attributed to the misexpression of Cdkn1c or other imprinted genes. To examine the role of misexpressions determined by two maternal copies of the Igf2/H19 imprinting control region (ICR)—a chromatin insulator, we introduced a mutant ICR (ICRΔ) into MatDup.dist7 fetuses. This activated Igf2, with correction of H19 expression and other imprinted transcripts expected. Substantial growth enhancement and full postnatal viability was obtained, demonstrating that the aberrant MatDup.dist7 phenotype is highly dependent on the presence of two unmethylated maternal Igf2/H19 ICRs. Activation of Igf2 is likely the predominant correction that rescued growth and viability. Further experiments involved the introduction of a null allele of Cdkn1c to alleviate its over-expression. Results were not consistent with the possibility that this misexpression alone, or in combination with Igf2 inactivity, mediates MatDup.dist7 death. Rather, a network of misexpressions derived from dist7 is probably involved. Our results are consistent with the idea that reduced expression of IGF2 plays a role in the aetiology of the human imprinting-related growth-deficit disorder, Silver-Russell syndrome

A haplotype map of allohexaploid wheat reveals distinct patterns of selection on homoeologous genomes

BACKGROUND: Bread wheat is an allopolyploid species with a large, highly repetitive genome. To investigate the impact of selection on variants distributed among homoeologous wheat genomes and to build a foundation for understanding genotype-phenotype relationships, we performed population-scale re-sequencing of a diverse panel of wheat lines. RESULTS: A sample of 62 diverse lines was re-sequenced using the whole exome capture and genotyping-by-sequencing approaches. We describe the allele frequency, functional significance, and chromosomal distribution of 1.57 million single nucleotide polymorphisms and 161,719 small indels. Our results suggest that duplicated homoeologous genes are under purifying selection. We find contrasting patterns of variation and inter-variant associations among wheat genomes; this, in addition to demographic factors, could be explained by differences in the effect of directional selection on duplicated homoeologs. Only a small fraction of the homoeologous regions harboring selected variants overlapped among the wheat genomes in any given wheat line. These selected regions are enriched for loci associated with agronomic traits detected in genome-wide association studies. CONCLUSIONS: Evidence suggests that directional selection in allopolyploids rarely acted on multiple parallel advantageous mutations across homoeologous regions, likely indicating that a fitness benefit could be obtained by a mutation at any one of the homoeologs. Additional advantageous variants in other homoelogs probably either contributed little benefit, or were unavailable in populations subjected to directional selection. We hypothesize that allopolyploidy may have increased the likelihood of beneficial allele recovery by broadening the set of possible selection targets

Variation of BMP3 Contributes to Dog Breed Skull Diversity

Since the beginnings of domestication, the craniofacial architecture of the domestic dog has morphed and radiated to human whims. By beginning to define the genetic underpinnings of breed skull shapes, we can elucidate mechanisms of morphological diversification while presenting a framework for understanding human cephalic disorders. Using intrabreed association mapping with museum specimen measurements, we show that skull shape is regulated by at least five quantitative trait loci (QTLs). Our detailed analysis using whole-genome sequencing uncovers a missense mutation in BMP3. Validation studies in zebrafish show that Bmp3 function in cranial development is ancient. Our study reveals the causal variant for a canine QTL contributing to a major morphologic trait

Reviewing the Empirical Evidence on Jury Racism: Findings of Discrimination or Discriminatory Findings?

I. Introduction II. Empirical Evidence of Jury Racism ... A. Laboratory Research ... B. Archival Research III. Evaluation of Evidence ... A. Limitations of Archival Research ... B. Methodological Limitations of Laboratory Research … C. Predictive Limitations of Laboratory Research ... D. Correspondence Limitations of Laboratory Research … E. Additional Laboratory Research IV. Conclusio

The psychological framing of cults: schematic representations and cult evaluations

This research investigates the hypothesis that perceptions of cult indoctrination techniques are based on negative schematic representations as opposed to objective evaluations. It is specifically suggested that individuals who are asked to evaluate cult indoctrination techniques are anchoring their judgments on the group label in contrast to the process being employed. Subjects were asked to read a description of a young man who joins a group and is exposed to its indoctrination process. Depending on the condition, subjects were led to believe that the group was either the Moonies, the Marines, or the Catholic Church. Except for the group label, in all three conditions the description of the indoctrination process was identical. Subjects were then asked to evaluate both the group's indoctrination techniques and the individual who joined the group, and to complete a questionnaire regarding their general knowledge of cults. Results indicate that subject ratings are significantly affected by the group label and that general knowledge regarding cults is based primarily on indirect sources. Implications of these findings are discussed

Ethics and the police-based researcher: reviewing the issues and obligations

This paper argues that the increased level of participation in research by police services has culminated in a parallel increase in the number of police-based researchers. These researchers, for the most part, are comprised of police personnel that develop, conduct, and assess research on issues related to crime and public safety. It is also clear that current ethics guidelines for police services seldom speak to issues related to research and that, often, government agencies such as the police are exempt from standard research protocols such as a required review by an Ethics Review Board. As such, it is suggested that police-based researchers, like social scientists, strive to understand and observe the basic ethical principles of research in order to maintain a high degree of scientific rigour as well as to ensure the safety and human rights of individuals involved in their research. Ethical issues regarding individuals as well as society are reviewed and their applications to police-based research are discussed

Developing effective community policing programs through a therapeutic jurisprudence model

This article suggests that there is a growing disconnect between the practice of community policing and the scientific examination and evaluation of the concept. Specifically, it is suggested that there is little empirical evidence available regarding the effectiveness of community policing initiatives and that, as a result, concerns have been raised regarding the development of these programs. The major challenges to developing community policing programs are reviewed and a therapeutic jurisprudence model is proposed as guidance for the development of future programs