Relativistic Coulomb Sum Rules for (e,e′)(e,e^\prime)

A Coulomb sum rule is derived for the response of nuclei to $(e,e^\prime)$ scattering with large three-momentum transfers. Unlike the nonrelativistic formulation, the relativistic Coulomb sum is restricted to spacelike four-momenta for the most direct connection with experiments; an immediate consequence is that excitations involving antinucleons, e.g., $N{\bar N}$ pair production, are approximately eliminated from the sum rule. Relativistic recoil and Fermi motion of target nucleons are correctly incorporated. The sum rule decomposes into one- and two-body parts, with correlation information in the second. The one-body part requires information on the nucleon momentum distribution function, which is incorporated by a moment expansion method. The sum rule given through the second moment (RCSR-II) is tested in the Fermi gas model, and is shown to be sufficiently accurate for applications to data.Comment: 32 pages (LaTeX), 4 postscript figures available from the author

Inelastic nucleon contributions in (e,e′)(e,e^\prime) nuclear response functions

We estimate the contribution of inelastic nucleon excitations to the $(e,e^\prime)$ inclusive cross section in the CEBAF kinematic range. Calculations are based upon parameterizations of the nucleon structure functions measured at SLAC. Nuclear binding effects are included in a vector-scalar field theory, and are assumed have a minimal effect on the nucleon excitation spectrum. We find that for q\lsim 1 GeV the elastic and inelastic nucleon contributions to the nuclear response functions are comparable, and can be separated, but with roughly a factor of two uncertainty in the latter from the extrapolation from data. In contrast, for q\rsim 2 GeV this uncertainty is greatly reduced but the elastic nucleon contribution is heavily dominated by the inelastic nucleon background.Comment: 20 pages, 7 figures available from the authors at Department of Physics and Astronomy, University of Rochester, Rochester NY 1462

Role of heavy-meson exchange in pion production near threshold

Recent calculations of $s$-wave pion production have severely underestimated the accurately known $pp\rightarrow pp\pi^0$\ total cross section near threshold. In these calculations, only the single-nucleon axial-charge operator is considered. We have calculated, in addition to the one-body term, the two-body contributions to this reaction that arise from the exchange of mesons. We find that the inclusion of the scalar $\sigma$-meson exchange current (and lesser contributions from other mesons) increases the cross section by about a factor of five, and leads to excellent agreement with the data. The results are neither very sensitive to changes in the distorting potential that generates the $NN$ wave function, nor to different choices for the meson-nucleon form factors. We argue that $pp\rightarrow pp\pi^0$\ data provide direct experimental evidence for meson-exchange contributions to the axial current.Comment: 28 Pages, IU-NTC #93-0

Inhibition of StearoylCoA Desaturase-1 Inactivates Acetyl-CoA Carboxylase and Impairs Proliferation in Cancer Cells: Role of AMPK

Cancer cells activate the biosynthesis of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) in order to sustain an increasing demand for phospholipids with appropriate acyl composition during cell replication. We have previously shown that a stable knockdown of stearoyl-CoA desaturase 1 (SCD1), the main Δ9-desaturase that converts SFA into MUFA, in cancer cells decreases the rate of lipogenesis, reduces proliferation and in vitro invasiveness, and dramatically impairs tumor formation and growth. Here we report that pharmacological inhibition of SCD1 with a novel small molecule in cancer cells promoted the activation of AMP-activated kinase (AMPK) and the subsequent reduction of acetylCoA carboxylase activity, with a concomitant inhibition of glucose-mediated lipogenesis. The pharmacological inhibition of AMPK further decreased proliferation of SCD1-depleted cells, whereas AMPK activation restored proliferation to control levels. Addition of supraphysiological concentrations of glucose or pyruvate, the end product of glycolysis, did not reverse the low proliferation rate of SCD1-ablated cancer cells. Our data suggest that cancer cells require active SCD1 to control the rate of glucose-mediated lipogenesis, and that when SCD1 activity is impaired cells downregulate SFA synthesis via AMPK-mediated inactivation of acetyl-CoA carboxylase, thus preventing the harmful effects of SFA accumulation

Inhibition of StearoylCoA Desaturase Activity Blocks Cell Cycle Progression and Induces Programmed Cell Death in Lung Cancer Cells

Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic lung cancer is ∼5%, hence alternative therapeutic strategies to treat this disease are critically needed. Recent studies suggest that lipid biosynthetic pathways, particularly fatty acid synthesis and desaturation, are promising molecular targets for cancer therapy. We have previously reported that inhibition of stearoylCoA desaturase-1 (SCD1), the enzyme that produces monounsaturated fatty acids (MUFA), impairs lung cancer cell proliferation, survival and invasiveness, and dramatically reduces tumor formation in mice. In this report, we show that inhibition of SCD activity in human lung cancer cells with the small molecule SCD inhibitor CVT-11127 reduced lipid synthesis and impaired proliferation by blocking the progression of cell cycle through the G1/S boundary and by triggering programmed cell death. These alterations resulting from SCD blockade were fully reversed by either oleic (18:1n-9), palmitoleic acid (16:1n-7) or cis-vaccenic acid (18:1n-7) demonstrating that cis-MUFA are key molecules for cancer cell proliferation. Additionally, co-treatment of cells with CVT-11127 and CP-640186, a specific acetylCoA carboxylase (ACC) inhibitor, did not potentiate the growth inhibitory effect of these compounds, suggesting that inhibition of ACC or SCD1 affects a similar target critical for cell proliferation, likely MUFA, the common fatty acid product in the pathway. This hypothesis was further reinforced by the observation that exogenous oleic acid reverses the anti-growth effect of SCD and ACC inhibitors. Finally, exogenous oleic acid restored the globally decreased levels of cell lipids in cells undergoing a blockade of SCD activity, indicating that active lipid synthesis is required for the fatty acid-mediated restoration of proliferation in SCD1-inhibited cells. Altogether, these observations suggest that SCD1 controls cell cycle progression and apoptosis and, consequently, the overall rate of proliferation in cancer cells through MUFA-mediated activation of lipid synthesis

Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease.

This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30% to 40%) and 100 mg/kg/day (100%). In the benznidazole- treated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80%). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole