Land Transport Emergency Response Technology Report

Sandia National Laboratories was tasked by the Japan Nuclear Cycle Development Institute (JNC) to provide assistance in developing an emergency response plan for radioactive material transportation activities. Those tasks included compiling radioactive materials (RAM) transportation accident data from the open literature and databases, investigating emergency response plans for radioactive materials transport in the United States, and developing specific recommendations for the JNC' nuclear material transport emergency response plan, based on information gathered during the first two tasks. These recommendations include developing a RAM database, a public transparency Internet website, an emergency response infrastructure designed specifically for transportation needs, and a clear set of directives to provide authority in the case of transportation accidents or incidents involving RAM

Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer.

Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R2 = 0.72, p < 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors

Identification of altered growth phenotypes in human breast cancer cells using cell culture methods that support growth of normal and neoplastic mammary epithelial cells

Over the past several years our laboratory has been studying factors that regulate proliferation of normal human mammary epithelial (HME) cells in order to better understand the alterations in cellular growth control mechanisms that occur during breast cancer development. To perform these experiments, we have either modified or developed cell culture methods for the isolation and growth of normal and neoplastic HME cells obtained from patient biopsy specimens. From these studies we have found that normal HME cells of the luminal lineage (the lineage from which breast cancer arises) have strict requirements for specific growth factor combinations for in vitro growth. Furthermore, these cells have a finite proliferative lifespan in culture. By contrast, human breast cancer (HBC) cells isolated from primary and metastatic sites exhibit many growth phenotypes that distinguish them from normal cells. First, whereas normal HME cells proliferate in culture with doubling times of 24–36 hours, HBC cells obtained from patient samples proliferate with doubling times of 100–200 hours. These proliferation kinetics are consistent with the rate at which these cells proliferate in vivo . This observation indicates that there are fundamental differences in growth regulation between normal and neoplastic mammary epithelial cells. Second, the majority of HBC cells isolated from human samples exhibit an extended proliferative lifespan in culture. Whereas normal HME cells undergo cell senescence after 15–20 population doublings, HBC cells often give rise to cell lines with indefinite proliferative potential. Third, HBC cells become independent of growth factors which are strictly required by normal HME cells for growth under defined conditions. In our experiments, escape from the requirements of exogenous epidermal growth factor (EGF) has been observed in cells from four patient-derived samples. Interestingly, the cellular mechanisms by which cells become EGF-independent for growth is different in cell lines isolated from different patients. Two breast cancer cell lines isolated in our laboratory proliferate continuously in serum-free, EGF-free medium and do not express EGF receptors. Thus, these cells are completely independent of EGF-mediated signalling pathways for their growth. A third cell line isolated in our laboratory has an amplified EGF receptor gene and overexpresses EGF receptor protein. Western blot analysis indicates that the tyrosine residues of the EGF receptor proteins in these cells are highly phosphorylated. These cells do not secrete any EGF-like growth factors that could be activating the receptors in an autocrine manner. This suggests that amplification and overexpression of EGF receptors can yield constitutively activated receptors that provide a mitogenic signal in the absence of a stimulatory ligand. Finally, we have analyzed the EGF requirements of human breast cancer cells that overexpress the erb B-2 receptor as a result of gene amplification. The results of these experiments indicated that overexpression of erb B-2 is, by itself, insufficient to overcome the EGF requirements of human breast cancer cells. However, one cell line that has a 15- to 20-fold amplification of erb B-2 and which expresses very high levels of tyrosine phosphorylated erb B-2 protein, is EGF-independent for growth. Thus, cell culture systems that allow proliferation of normal HME cells and HBC cells under well-defined culture conditions can result in identification of altered growth phenotypes associated with the neoplastic progression of breast cancer cells. In addition, isolation of cells exhibiting altered growth phenotypes may lead to insights as to the genetic mechanisms resulting in altered growth regulation in breast cancer cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38456/1/240531151_ftp.pd

The lncRNA landscape of breast cancer reveals a role for DSCAM-AS1 in breast cancer progression.

Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer

Conservative management of Paget disease of the breast with radiotherapy

BACKGROUND At 5-year follow-up, patients with Paget disease of the breast who were treated with breast-conserving surgery (BCS) and radiotherapy (RT) had excellent results. The current report provides 10- and 15-year rates of tumor control in the breast, as well as disease-free and overall survival rates following BCS and RT in a cohort of patients with Paget disease presenting without a palpable mass or mammographic density. METHODS Through a collaborative review of patients treated with BCS and RT from seven institutions, 38 cases of Paget disease of the breast presenting without a palpable mass or mammographic density were identified. All patients had pathologic confirmation of typical Paget cells at time of diagnosis. Thirty-six of 38 patients had a minimum follow-up greater than 12 months and constitute the study cohort. Ninety-four percent of patients underwent complete or partial excision of the nipple-areola complex and all patients received a median external beam irradiation dose of 50 Gy (range, 45–54 Gy) to the whole breast. Ninety-seven percent of patients also received a boost to the remaining nipple or tumor bed, a median total dose of 61.5 Gy (range, 50.4–70 Gy). RESULTS With median follow-up of 113 months (range, 18–257 months), 4 of 36 patients (11%) developed a first recurrence of disease in the treated breast only. Two of the four recurrences in the breast were ductal carcinoma in situ (DCIS) only and two were invasive with DCIS. Two additional patients had a recurrence in the breast as a component of first failure. Actuarial local control rates for the breast as the only site of first recurrence were 91% at 5 years (95% confidence interval [CI], 80–100%) and 87% (95% CI, 75–99%) at both 10 and 15 years. Actuarial local control rates for breast recurrence, as a component of first failure, were 91% (95% CI, 80–100%), 83% (95% CI, 69–97%), and 76% (95% CI, 58–94%) at 5, 10, and 15 years, respectively. No clinical factors were identified as significant predictors for breast recurrence. Five-, 10- and 15-year actuarial rates for survival without disease of 97% (95% CI, 90–100%) and 5-, 10-, and 15-year actuarial rates of overall survival of 93% (95% CI, 84–100%) at 5 years and 90% (95% CI, 78–100%) at 10 and 15 years were reported. CONCLUSIONS These data confirm excellent rates of local control, disease-free survial, and overall survival at 10 and 15 years following BCS and RT for Paget disease of the breast. This study continues to support the recommendation of local excision and definitive breast irradiation as an alternative to mastectomy in the treatment of patients with Paget disease presenting without a palpable mass or mammographic density. Cancer 2003;97:2142–9. © 2003 American Cancer Society. DOI 10.1002/cncr.11337Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34369/1/11337_ftp.pd

An academic health center cost analysis of screening mammography

BACKGROUND The current study sought to determine the institutional financial impact of a screening mammography (SM) program in the context of an integrated cancer center. METHODS Using administrative databases, 10,048 women were identified as receiving screening mammograms in fiscal year 1999 and the first one-half of fiscal year 2000. The utilization of breast care resources was followed for an average of 1208 days. The University of Michigan cost accounting system was then used to determine overall margin (revenues − total costs) and contribution margin (revenues − actual costs) of the SM program, as well as other breast care services. RESULTS The percentage of variable costs to total costs for the SM program was 24%. The overall facility losses in the breast care line were $1.7 million with a positive contribution margin of$2.0 million. The annual yield of nonscreening/diagnostic mammographic procedures was 0.9%. All types of radiologic activity failed to cover their total costs, but did provide a positive contribution margin. Overall margins for surgery procedures were approximately even, and adjuvant medical and radiotherapy services were net positive. Modeling helped to identify overhead limits necessary to achieve margin targets associated with increased activity. CONCLUSIONS The current study showed that SM programs are unlikely to succeed financially without careful selection of those screened to increase the yield of diagnostic and therapeutic procedures. Based on favorable contribution margins, SM programs were viable when viewed as incremental business. Cancer 2004. © 2004 by the American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34389/1/20476_ftp.pd

Draft Genome Sequence of \u3ci\u3eErwinia tracheiphila\u3c/i\u3e, an Economically Important Bacterial Pathogen of Cucurbits

Erwinia tracheiphila is one of the most economically important pathogens of cucumbers, melons, squashes, pumpkins, and gourds in the northeastern and midwestern United States, yet its molecular pathology remains uninvestigated. Here, we report the first draft genome sequence of an E. tracheiphila strain isolated from an infected wild gourd (Cucurbita pepo subsp. texana) plant. The genome assembly consists of 7 contigs and includes a putative plasmid and at least 20 phage and prophage elements

Clinical and Radiologic Assessments to Predict Breast Cancer Pathologic Complete Response to Neoadjuvant Chemotherapy

To prospectively compare the ability of clinical examination, mammography, vascularity-sensitive ultrasound, and magnetic resonance imaging (MRI) to determine pathologic complete response (CR) in breast cancer patients undergoing neoadjuvant chemotherapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44230/1/10549_2005_Article_2510.pd

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder