Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas

Abstract Introduction Genomic alterations have been observed in breast carcinomas that affect the capacity of cells to regulate proliferation, signaling, and metastasis. Re-sequence studies have investigated candidate genes based on prior genetic observations (changes in copy number or regions of genetic instability) or other laboratory observations and have defined critical somatic mutations in genes such as TP53 and PIK3CA. Methods We have extended the paradigm and analyzed 21 genes primarily identified by expression profiling studies, which are useful for breast cancer subtyping and prognosis. This study conducted a bidirectional re-sequence analysis of all exons and 5', 3', and evolutionarily conserved regions (spanning more than 16 megabases) in 91 breast tumor samples. Results Eighty-seven unique somatic alterations were identified in 16 genes. Seventy-eight were single base pair alterations, of which 23 were missense mutations; 55 were distributed across conserved intronic regions or the 5' and 3' regions. There were nine insertion/deletions. Because there is no a priori way to predict whether any one of the identified synonymous and noncoding somatic alterations disrupt function, analysis unique to each gene will be required to establish whether it is a tumor suppressor gene or whether there is no effect. In five genes, no somatic alterations were observed. Conclusion The study confirms the value of re-sequence analysis in cancer gene discovery and underscores the importance of characterizing somatic alterations across genes that are related not only by function, or functional pathways, but also based upon expression patterns

Investigation of Tc Migration Mechanism During Bulk Vitrification Process Using Re Surrogate

As a part of Bulk vitrification (BV) performance enhancement tasks, Laboratory scoping tests were performed in FY 2004-2005 to explore possible ways to reduce the amount of soluble Tc in the BV waste package. Theses scoping tests helped identify which mechanisms play an important role in the migration of Tc in the BV process (Hrma et al. 2005 and Kim et al. 2005). Based on the results from these scoping tests, additional tests were identified that will improve the understanding of Tc migration and to clearly identify the dominant mechanisms. The additional activities identified from previous studies were evaluated and prioritized for planning for Tasks 29 and 30 conducted in FY2006. Task 29 focused on the improved understanding of Tc migration mechanisms, and Task 30 focused on identifying the potential process changes that might reduce Tc/Re migration into the castable refractory block (CRB). This report summarizes the results from the laboratory- and crucible-scale tests in the lab for improved Tc migration mechanism understanding utilizing Re as a surrogate performed in Task 29

Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition

Impacts of increasing anthropogenic soluble iron and nitrogen deposition on ocean biogeochemistry

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 23 (2009): GB3016, doi:10.1029/2008GB003440.We present results from transient sensitivity studies with the Biogeochemical Elemental Cycling (BEC) ocean model to increasing anthropogenic atmospheric inorganic nitrogen (N) and soluble iron (Fe) deposition over the industrial era. Elevated N deposition results from fossil fuel combustion and agriculture, and elevated soluble Fe deposition results from increased atmospheric processing in the presence of anthropogenic pollutants and soluble Fe from combustion sources. Simulations with increasing Fe and increasing Fe and N inputs raised simulated marine nitrogen fixation, with the majority of the increase in the subtropical North and South Pacific, and raised primary production and export in the high-nutrient low-chlorophyll (HNLC) regions. Increasing N inputs alone elevated small phytoplankton and diatom production, resulting in increased phosphorus (P) and Fe limitation for diazotrophs, hence reducing nitrogen fixation (∼6%). Globally, the simulated primary production, sinking particulate organic carbon (POC) export. and atmospheric CO2 uptake were highest under combined increase in Fe and N inputs compared to preindustrial control. Our results suggest that increasing combustion iron sources and aerosol Fe solubility along with atmospheric anthropogenic nitrogen deposition are perturbing marine biogeochemical cycling and could partially explain the observed trend toward increased P limitation at station ALOHA in the subtropical North Pacific. Excess inorganic nitrogen ([NO3 −] + [NH4 +] − 16[PO4 3−]) distributions may offer useful insights for understanding changing ocean circulation and biogeochemistry.This work was supported by funding from NSF grant OCE-0452972 to J. K. Moore and C. S. Zender. Computations were supported by the Earth System Modeling Facility at UCI (NSFATMO321380) and by the Climate Simulation Laboratory at National Center for Atmospheric Research. The National Center for Atmospheric Research is sponsored by the U.S. National Science Foundation. N.M. would like to acknowledge the assistance of NSF– Carbon and Water (ATM-0628472), and N.M., S.D., and C.L. would like to acknowledge the assistance of NASA-IDS (NNX07AL80G)

A genome-wide association study of marginal zone lymphoma shows association to the HLA region

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P - 3.95 x 10(-15)) and HLA-B (rs2922994, P - 2.43 x 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility

Money: A Market Microstructure Approach

The current discussion about the future of the financial system draws heavily on a set of theories known as the ‘New Monetary Economics’. The New Monetary Economics predicts that deregulation and financial innovation will lead to a moneyless world. This paper uses a market microstructure approach to show that a common medium of exchange that serves as unit of account will remain a necessary instrument to reduce transaction costs. This finding is supported by empirical evidence from foreign exchange markets