Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10 ) and AC058822.1 (P = 1.47 × 10 ), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10 ), demonstrating the importance of diversifying study cohorts. [Abstract copyright: © 2023. The Author(s).

Metastatic epidural spinal cord compression: current concepts and treatment

Metastatic epidural spinal cord compression (MESCC) is a medical emergency complicating the course of 5–10% of patients with cancer [1]. When diagnosis and treatment is early with the patient ambulatory prognosis for continued ambulation is good [2]. If the patient is nonambulatory or paraplegic, prognosis for meaningful recovery of motor and bladder function is markedly decreased. In the last decade, significant advances in the understanding, management and treatment of metastatic epidural spinal cord compression have occurred.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45378/1/11060_2005_Article_BF01051052.pd

Phonological theories meet sign language: two theories of the two hands

We explore two models of the nonpreference hand in sign language phonology. These models are fully developed by the authors elsewhere. Here, we compare and contrast the models, paying special attention to the relationship between the models and the theories behind them. In the process, we address questions of broad theoretical interest: (I) Does the existence of two anatomically similar articulators in sign languages require a phonological model that is fundamentally different from models of spoken language? (2) In what ways does the particular phonological theory adopted shape the investigation and its results? The model of Sandler (1989, 1994a) is motivated by theories of Feature Geometry (e.g., Clements 1985), while that of van der Hulst (1993, to appear) is motivated by principles of Dependency Phonology. These theories are not. mutually exclusive, but each approaches the issue of phonological structure from a somewhat different perspective. We. show that each model of the nonpreference hand has certain advantages over the other in account-ing for the sign language data, and that the two models have independent theoretical and empirical consequences as well. In each model, the presence of two similar articulators, leads to structural differences between signed and spoken languages, but in neither case do these differences violate general principles of phonological structure. That is, each phoonological theory can accommodate the facts in a principled way. We find that each model serves to explain somewhat different properties of the aspects of sign language phonology examined. The particular phenomena that we analyze do not conclusively select one phonological theory over the other, but we do not see this as a shortcoming of the investigation. On the contrary, our results indicate that adopting different theories for sound reasons can expand our understanding of phonological phenomena, while at the same time shedding light on the scope and explanatory power of the theories