The “Spot 14” Gene Resides on the Telomeric End of the 11q13 Amplicon and is Expressed in Lipogenic Breast Cancers: Implications for Control of Tumor Metabolism

Enhanced long chain fatty acid synthesis may occur in breast cancer, where it is necessary for tumor growth and predicts a poor prognosis. “Spot 14” (S14) is a carbohydrate- and thyroid hormone-inducible nuclear protein specific to liver, adipose, and lactating mammary tissues that functions to activate genes encoding the enzymes of fatty acid synthesis. Amplification of chromosome region 11q13, where the S14 gene (THRSP) resides, also predicts a poor prognosis in breast tumors. We localized the S14 gene between markers D11S906 and D11S937, at the telomeric end of the amplified region at 11q13, and found that it was amplified and expressed in breast cancer-derived cell lines. Moreover, concordant expression of S14 and a key lipogenic enzyme (acetyl-CoA carboxylase) in a panel of primary breast cancer specimens strongly supported a role for S14 as a determinant of tumor lipid metabolism. S14 expression provides a pathophysiological link between two prognostic indicators in breast cancer: enhanced lipogenesis and 11q13 amplification

High Repetition Rate, LINAC-Based Nuclear Resonance Fluorescence FY 2008 Final Report

This summarizes the first year of a multi-laboratory/university, multi-year effort focusing on high repetition rate, pulsed LINAC-based nuclear resonance fluorescence (NRF) measurements. Specifically, this FY2008 effort centered on experimentally assessing NRF measurements using pulsed linear electron accelerators, operated at various repetition rates, and identifying specific detection requirements to optimize such measurements. Traditionally, interest in NRF as a detection technology, which continues to receive funding from DHS and DOE/NA-22, has been driven by continuous-wave (CW), Van de Graff-based bremsstrahlung sources. However, in addition to the relatively sparse present-day use of Van de Graff sources, only limited NRF data from special nuclear materials has been presented; there is even less data available regarding shielding effects and photon source optimization for NRF measurements on selected nuclear materials

Missing data approaches in longitudinal studies of aging: A case example using the National Health and Aging Trends Study

Purpose Missing data is a key methodological consideration in longitudinal studies of aging. We described missing data challenges and potential methodological solutions using a case example describing five-year frailty state transitions in a cohort of older adults. Methods We used longitudinal data from the National Health and Aging Trends Study, a nationally-representative cohort of Medicare beneficiaries. We assessed the five components of the Fried frailty phenotype and classified frailty based on their number of components (robust: 0, prefrail: 1–2, frail: 3–5). One-, two-, and five-year frailty state transitions were defined as movements between frailty states or death. Missing frailty components were imputed using hot deck imputation. Inverse probability weights were used to account for potentially informative loss-to-follow-up. We conducted scenario analyses to test a range of assumptions related to missing data. Results Missing data were common for frailty components measured using physical assessments (walking speed, grip strength). At five years, 36% of individuals were lost-to-follow-up, differentially with respect to baseline frailty status. Assumptions for missing data mechanisms impacted inference regarding individuals improving or worsening in frailty. Conclusions Missing data and loss-to-follow-up are common in longitudinal studies of aging. Robust epidemiologic methods can improve the rigor and interpretability of aging-related research

Four Competing Definitions of Morphine Equivalence Insidiously Inhibit Evidence Synthesis

Analysis of opioid milligrams of morphine equivalents (MME) per day definitions. Presented virtually at the 37th annual International Conference on Pharmacoepidemiology and Therapeutic Risk Management

MPACT Fast Neutron Multiplicity System Design Concepts

This report documents work performed by Idaho National Laboratory and the University of Michigan in fiscal year (FY) 2012 to examine design parameters related to the use of fast-neutron multiplicity counting for assaying plutonium for materials protection, accountancy, and control purposes. This project seeks to develop a new type of neutron-measurement-based plutonium assay instrument suited for assaying advanced fuel cycle materials. Some current-concept advanced fuels contain high concentrations of plutonium; some of these concept fuels also contain other fissionable actinides besides plutonium. Because of these attributes the neutron emission rates of these new fuels may be much higher, and more difficult to interpret, than measurements made of plutonium-only materials. Fast neutron multiplicity analysis is one approach for assaying these advanced nuclear fuels. Studies have been performed to assess the conceptual performance capabilities of a fast-neutron multiplicity counter for assaying plutonium. Comparisons have been made to evaluate the potential improvements and benefits of fast-neutron multiplicity analyses versus traditional thermal-neutron counting systems. Fast-neutron instrumentation, using for example an array of liquid scintillators such as EJ-309, have the potential to either a) significantly reduce assay measurement times versus traditional approaches, for comparable measurement precision values, b) significantly improve assay precision values, for measurement durations comparable to current-generation technology, or c) moderating improve both measurement precision and measurement durations versus current-generation technology. Using the MCNPX-PoliMi Monte Carlo simulation code, studies have been performed to assess the doubles-detection efficiency for a variety of counter layouts of cylindrical liquid scintillator detector cells over one, two, and three rows. Ignoring other considerations, the best detector design is the one with the most detecting volume. However, operational limitations guide a) the maximum acceptable size of each detector cell (due to PSD performance and maximum-acceptable per-channel data throughput rates, limited by pulse pile-up and the processing rate of the electronics components of the system) and b) the affordability of a system due to the number of total channels of data to be collected and processed. As a first estimate, it appears that a system comprised of two rows of detectors 5" Ø ? 3" would yield a working prototype system with excellent performance capabilities for assaying Pu-containing items and capable of handling high signal rates likely when measuring items with Pu and other actinides. However, it is still likely that gamma-ray shielding will be needed to reduce the total signal rate in the detectors. As a first step prior to working with these larger-sized detectors, it may be practical to perform scoping studies using small detectors, such as already-on-hand 3" Ø ? 3" detectors

Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma

BACKGROUND: Germline mutations in RET are responsible for multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia/adenoma. Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic VHL gene alterations are also important in the pathogenesis of MEN2-associated MTC. METHODS: We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and RET germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and VHL mutation analysis. RESULTS: First, we searched for allelic imbalance between mutant and wild-type RET by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for RET amplification by this technique could be demonstrated in 3 of 6 MTCs. We then performed LOH analysis using D3S1038 and D3S1110 which map to the VHL gene locus at 3p25/26. VHL gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type RET. Mutation analysis of the VHL gene showed a somatic frameshift mutation in 1 MTC that also demonstrated LOH at 3p25/26. In the 2 other MTCs with allelic imbalance of RET and somatic VHL gene deletion, no somatic VHL mutation could be detected. The CCH specimen did neither reveal RET imbalance nor somatic VHL gene alterations. CONCLUSION: These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC

Lipoprotein Lipase Links Dietary Fat to Solid Tumor Cell Proliferation

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain pre-formed, diet-derived fatty acids by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further demonstrate that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or fatty acid uptake will be necessary to target the requirement of cancer cells for FA