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Human pancreatic adenocarcinoma is a major leading cause of cancer mortality in the United States. Given that current strategies are relatively ineffective against this disease, new treatments are being developed. Liposomes possessing relatively high cationic lipid content preferentially accumulate in tumor angiogenic vessels compared to vessels in normal tissues. We therefore seek to develop cationic liposomes for targeting pancreatic tumor vessels.We report development of 5-fluorouracil (5-FU) and doxorubicin hydrochloride (DOX) loaded in PEGylated cationic liposomes (PCLs). We evaluate cell association, intracellular fate, and cytotoxicity. Human pancreatic cancer cells HPAF-II and Capan-1, and endothelial cells HMEC-1 and HUVEC were used in this study. Intratumoral distribution of PCLs in (HPAF-II) tumors was determined by intravital microscopy.HUVEC and HMEC-1 were most susceptible to 5-FU after 24 and 48 h, compared to HPAF-II and Capan-1. We observed90% incorporation of 5-FU and DOX in PCLs for 3-20 mol% preparations, with reduced incorporation for20 mol% formulations. PCLs showed significantly higher association with human endothelial versus pancreatic cancer cells, and improved growth inhibitory properties of DOX. Intravital microscopy revealed distribution of PCLs along HPAF-II vessels.Targeting human pancreatic cancer with PCLs may represent a rational alternative to conventional strategies.

We have studied the feasibility of using the 3D fully electromagnetic implicit hybrid particle code LSP (Large Scale Plasma) to study laser plasma interactions with dense, compressed plasmas like those created with Z, and which might be created with the planned ZR. We have determined that with the proper additional physics and numerical algorithms developed during the LDRD period, LSP was transformed into a unique platform for studying such interactions. Its uniqueness stems from its ability to consider realistic compressed densities and low initial target temperatures (if required), an ability that conventional PIC codes do not possess. Through several test cases, validations, and applications to next generation machines described in this report, we have established the suitability of the code to look at fast ignition issues for ZR, as well as other high-density laser plasma interaction problems relevant to the HEDP program at Sandia (e.g. backlighting).

Tumor vessels possess unique physiological features that might be exploited for improving drug delivery. In the present study, we investigate the possibility of modifying polyethylene glycol-ylated liposome cationic charge of polyethylene glycol coated liposomes to optimize delivery to tumor vessels using biodistribution studies and intravital microscopy. The majority of liposomes accumulated in the liver, and increasing charge resulted in lower retention in the spleen and blood. Although overall tumor uptake was not affected by charge in the biodistribution studies, intravital microscopy showed that increasing the charge content from 10 to 50 mol % doubled the accumulation of liposomes in tumor vessels, suggesting a change in intratumor distribution; no significant effect of charge on interstitial accumulation could be detected, possibly attributable to spatial heterogeneity. Increased vascular accumulation of cationic liposomes was similar in two different tumor types and sites. Our results suggest that optimizing physicochemical properties of liposomes that exploit physiological features of tumors and control the intratumor distribution of these drug carriers should improve vascular-specific delivery.

The molecular site of anesthetic action remains an area of intense research interest. It is not clear whether general anesthetics act through direct binding to proteins or by perturbing the membrane properties of excitable tissues. Several studies indicate that anesthetics affect the properties of either membrane lipids or proteins. However, gaps remain in our understanding of the molecular mechanism of anesthetic action. Recent developments in membrane biology have led to the concept of small-scale domain structures in lipid and lipid–protein coupled systems. The role of such domain structures in anesthetic action has not been studied in detail. In the present study, we investigated the effect of anesthetics on lipid domain structures in model membranes using the fluorescent spectral properties of Laurdan (6-dodecanoyl-2-dimethylamino naphthalene). Propofol, a general anesthetic, promoted the formation of fluid domains in model membranes of dipalmitoyl phosphatidyl choline (DPPC) or mixtures of lipids of varying acyl chains (DPPC:DMPC dimyristoyl phosphatidyl choline 1:1). The estimated size of these domains is 20–50 A. Based on these studies, we speculate that the mechanism of anesthetic action may involve effects on protein–lipid coupled systems through alterations in small-scale lipid domain structures.

Background: Interstitial and vascular targeting with cytotoxic agents has proven to be an effective approach for cancer therapy (1). Ceramide, a sphingolipid, plays an important role in apoptosis, regulation of differentiation, growth suppression, and in cell senescence (2). Liposomes containing ceramide exert an anti-proliferative effect against the growth of tumor cells in vitro (3). In this study, we attempted to apply a rational approach to the development of ceramide liposomes for tumor targeting. Methods: We first determined the relative amounts of ceramide produced by cells normally found in the tumor interstitial matrix (ZR-75-1- human breast cancer cells), and by those lining tumor endothelia (HMEC-1 -human microvascular endothelial cells). For this experiment we measured sphingomyelinase activity. We next determined the cytotoxic effects of various liposome systems containing 0 to 20% ceramide (C6:1) content. The optimal ceramide content was determined from this study, and 2-methoxyestradiol (2-ME) was loaded in the optimal ceramide liposome preparation type. We next evaluated cytotoxic effects of the drug-loaded liposomes compared to ceramide liposomes alone. Results: ZR-75-1 cells showed a higher level of sphingomyelinase activity (4.4 fold) as compared to that of HMEC-1. The 20% ceramide formulation demonstrated the most significant anti-proliferative effect, regardless of the cell line. The cytotoxic drug effects were favorably influenced by the ceramide content. Finally, preliminary studies suggest that the overall effectiveness of ceramide liposomes against the growth of proliferating tumor cells correlated with the sphingomyelinase activity expressed by the target cells. Conclusion: Future studies will determine whether sphingomyelinase activity can be used to determine the population of cells (i.e., interstitial vs vascular) most likely to benefit from ceramide (cytotoxic) drug-loaded liposomes as a therapeutic approach. Citation Format: Shaohua Cheng, William Crall, Bryan Nguyen, Charles Dang, Musaed Alkholief, Robert B. Campbell. Development of ceramide liposomes for tumor interstitial and vascular drug targeting. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4473. doi:10.1158/1538-7445.AM2014-4473

Introduction: Solid tumors comprise more than 85% of cancers that affect humans. The presence of the extracellular matrix, namely mucin, on the tumor cell is considered one of the barriers against effective treatment of solid tumors. In tumor cells, mucin is aberrantly overexpressed producing a mucin mesh which may impede the rate of entry of chemotherapy medications. The type O-glycosylation inhibitor, benzyl-α-GalNAc, significantly reduces mucin type O-glycosylation in mucin-producing tumor cells resulting in enhanced cytotoxic drug action. We next seek to determine the role of mucin in the delivery of nano-sized drug delivery systems. Methods: The cell lines used were derived from tumor or normal tissues representing multiple organ environments. These cell lines include: Capan-1, Capan-2, PANC-1, HPAF-II (human adenocarcinoma), hTERT-HPNE (normal human pancreas), CRL-1777 (normal murine pancreas), ZR-75-1 (breast cancer), and CRL-2089 (normal breast). Evaluation of MUC1 protein expression was done by western blot analysis in addition to fluorescence microplate reader using CD227 (anti-MUC1 antibody). Furthermore, we investigated the cellular uptake of the fluorescently labeled polystyrene microsphere beads and liposomes in the different cell lines. Finally, FACS analysis was used to determine cellular uptake following inhibition of mucin type O-glycosylation and compared to control. Results: Different levels of mucin expression were observed among the various cell lines. By investigating the antibody association with the MUC1 protein core, Capan-1and ZR-75-1have shown the greatest cellular uptake following inhibition of glycosylation. To evaluate the cellular uptake of the microsphere beads and liposomes we used cell lines derived from the pancreas. The glycosylation inhibitor had little to no effect on the uptake of the microsphere beads, regardless of cell line employed. However, the overall uptake of the large beads (990 nm) was significantly greater in comparison to the uptake of the smaller beads (67 and 116 nm). Next, we carried out the same procedure using liposomes that were made in the size range of 60-80nm, 100-120nm, and 350-550nm. Out of the 6 pancreatic cell lines examined, PANC-1 cell line showed that the uptake of each liposome preparation type was significantly greater following the inhibition of mucin glycosylation. In addition, we observed that the uptake of liposomes increased as a function of liposome size. This was confirmed by FACS analysis as well. Conclusion: Our results suggest that inhibiting the mucin type O- glycosylation alters the uptake of the microsphere beads in all the cell lines examined. As for the liposomes, however, the effect of inhibiting glycosylation is cell line dependent. Further studies will be performed to investigate the factors underlying the differential uptake observed with liposomes following inhibition of glycosylation. This might be helpful in developing a better nano-therapeutic approach to treat cancer. Citation Format: Musaed A. Alkholief, Robert Campbell. An evaluation of the role of mucin in nano drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4469. doi:10.1158/1538-7445.AM2014-4469

Conventional epifluorescence microscopy coupled with chronic animal window models has provided stunning insight into tumor pathophysiology, including gene expression, angiogenesis, interstitial transport, and drug delivery. However, the findings to date have been limited to the tumor surface (

We have developed magnetic nano-liposomes (MNL), incorporating superparamagnetic iron oxide nanoparticles (SPION), that are versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. MNL are prepared with a formuation of DPPC:DOTAP:CHOL and DOPE-PEG5000. Incorporation of SPIONs results in MNL with mean diameter of 150-250 nm. MNL are easily taken up by B16-F10 melanoma, HUMVEC-D and breast cancer cell lines. They preferentially target the tumor vasculature as shown in a dorsal skin fold chamber using fluorescently labeled MNL. MNL display superparamagnetic response that is essential for magnetic targeting, MR contrast enhancement and magnetic heating. MNL was administrated to SCID mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre-injection and post-injection MR images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by 111In labeled MNL and amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations. We have shown that tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2-fold greater accumulation by magnetic targeting. 111In radio-labeled MNL have been shown to enable multi-modal imaging in vivo using MRI and SPeCT/CT. The images show that an MNL bolus injected intra-tumorally was retained in the tumor 24 hours after injection. Application of a magnetic field enables redistribution of the MNL in the tumor. These MNL are also responsive to ac magnetic fields applied using a Copper coil at 360 kHz and 170A driving current. Both hyperthermia (upto 45C) and thermo-ablative temperatures upto 90C were achieved in 10 – 30 minutes ex vivo in buffer. The results indicate high efficiency for magnetic heating using MNL (Specific Absorption Rate ∼ 104 W/kg) and demonstrate the capability to couple ac magnetic fields to MNL to achieve any set of temperatures needed for hyperthermia and thermal ablation. To date there are no truly theranostic platforms that have been approved for clinical use that combine targeting, thermal heating and MRI imaging capabilities. Existing FDA approved magnetic nanoparticle formulations like ferridex and ferumoxytol, are optimized for MR imaging, and have not been shown to be usable for thermal therapy.The MNL platform is a novel nanoplatform combining multi-modal imaging capabilities, with magnetic targeting and thermal therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2011-380

The following experiment determined whether the estrogenic suppression of food intake is dependent upon changes in protein synthesis within neurons of the paraventricular nucleus of the hypothalamus (PVN). Ovariectomized rats were treated centrally with anisomycin-filled or empty (control) cannulae in the PVN. Females were injected with either 2.0 μg of estradiol benzoate (EB) or the oil vehicle and the inner cannulae were removed 2 h later. EB injections significantly lowered food and water intake in the central control group but not in animals given PVN implants of anisomycin. Body weight gain decreased for all females. EB induced comparable levels of female sexual behavior in both groups, demonstrating that anisomycin implants did not affect the ability of estradiol to stimulate lordosis. These findings indicate that the effects of estradiol on food intake require the activation of protein synthesis in estrogen-sensitive PVN neurons.

Uptake of cytotoxic drugs by typical tumor cells is limited by the dense dendritic network of oligosaccharide mucin chains that forms a mechanical barrier. Atomic force microscopy is used to directly measure the force needed to pierce the mucin layer to reach the cell surface. Measurements are analyzed by de Gennes’ steric reptation theory. Multidrug resistant ovarian tumor cells shows significantly larger penetration load compared to the wide type. A pool of pancreatic, lung, colorectal, and breast cells are also characterized. The chemotherapeutic agent, benzyl-α-GalNac, for inhibiting glycosylation is shown to be effective in reducing the mechanical barrier.

Purpose: The development of non‐invasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. Magnetic Cationic Liposomes (MCL) that carry a cargo of anti‐cancer drugs and magnetic nanoparticles that will selectively target primary and metastatic cancertumorsdeliver drugs to them and visualize their effects through magnetic resonance imaging(MRI)single photon emission computed tomography(SPECT) and fluorescence spectroscopy. The aim of the present study is to evaluate MCL as a versatile theranostic nanoplatform for enhanced drug deliveryimaging and monitoring of cancer treatment. Materials and Method: Poly‐ethyleneglycol (PEG) coated cationic liposomes are loaded with superparamagnetic iron oxide nanoparticles (SPIONS) and tagged with the radioisotope Indium‐111. MCL was administered to SCID mouse with metastatic (B16‐F10) melanoma grown in the right flank. Pre‐injection and post‐injection MR and SPECT/CT images were used to assess response to magnetic targeting effects and tumor and organ distribution. Results:Tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2‐fold greater accumulation by magnetic targeting. SPECT/CT images showed the localization and distribution of MCL in the tumor.Conclusion: MR SPECT/CT and biodistribution analyses clearly show the efficacy of MCL as MRI contrast agents prove the use of magnetic guidance and demonstrate the potential of MCL as agents for imaging guidance and therapeutic delivery.

Achieving a high degree of radiation symmetry is a critical feature of target designs for indirect-drive inertial confinement fusion. Typically, the radiation flux incident on the capsule is required to be uniform to 1% or better. It is generally possible to design a hohlraum that provides low values of higher-order asymmetry (Legendre mode P10 and above) due to geometric averaging effects. Because low-order intrinsic asymmetry (e.g., Legendre modes P2 and P4) are less strongly reduced by geometric averaging alone, the development of innovative control techniques has been an active area of research in the inertial fusion community over the years. Shields placed inside the hohlraum are one example of a technique that has often been proposed and incorporated into hohlraum target designs. Simple mathematical considerations are presented indicating that radiation shields may be designed to specifically tune lower-order modes (e.g., P4) without deleterious effects on the higher order modes. Two-dimensional vie...

Differences in suckering from root segments and in rooting from sucker cuttings were studied among four species of Populus, including three poplars, P. angustifolia James, P. deltoides Bartr., and P. balsamifera L., and an aspen, P. tremuloides Michx. Places where suckers originated on root segments were more variable in the poplars than in the aspen. Whereas suckers developed in the aspen only from the periderm, suckers developed in the poplars from the periderm and from cambium exposed at the cut ends of segments and lateral roots. Poplar suckers arising from the periderm originated from preexisting suppressed buds embedded in the periderm. Suckers developed in the aspen from preexisting primordia. Lateral root formation from preexisting and newly initiated meristems on root segments was common in the poplars but rare in the aspen. The presence of lateral roots increased sucker growth, and the development of suckers and lateral roots responded to the inherent polarity of the root segment. Sucker cuttings from the poplars were generally superior in rooting capacity to those from the aspen.

Bollworm, Heliothis zea Boddie, moth emergence was measured from a sandy loam soil after increasing levels of soil compaction. Soil strength as measured by indentation probe resistance in kg/cm2 was measured at successive depths under each level of compaction and related to the moth emergence pattern. Possible physical damage to pupae and the condition of the pupal chamber by the compaction process was determined by placing individual insects in cylindrical containers of soil, compacting the soil in the containers, and then excavating the pupae. Moth emergence decreased significantly with increasing soil compaction and also showed a definite relationship to the pattern of soil compaction vs. depth. Excavation of pupae from compacted soil indicated that soil compaction, rather than physical damage to the pupae, was the primary cause of reduced moth emergence.

Silicon carbide has been used extensively as an abrasive, but only in the last 25 years has its potential as a semiconductor been exploited. The rationale for SiC semiconductor devices is their high temperature performance. Rectifiers, field effect transistors, charged particle detectors, and other devices operate efficiently at temperatures about 800 K.

This paper analyzes the effects of three alternative rules on the long-run distributions of both the spot and futures prices ina single commodity market, in which the key behavioral relationships are derived from the optimizing behavior of producers and speculators.The rules considered include: (i) leaning against the wind in the spot market; (ii) utility maximizing speculative behavior by the stabilization authority in the futures market; (iii) leaning against the wind in the futures market. Since the underlying model is sufficiently complex to preclude analytical solutions, the analysis makes extensive use of simulation methods. As a general proposition we find that intervention in the futures market is not as effective in stabilizing either the spot price of the futures price as is intervention in the spot market. Indeed, Rule (iii), while stabilizing the futures price may actually destabilize the spot price. Furthermore, the analogous type of rule undertaken in the spot market will always stabilize the futures price to a greater degree than it does the spot price. The welfare implications of these rules are also discussed. Our analysis shows how these can generate rather different distributions of welfare gains, including the overall benefits.

• A reproducible model of severe herpetic interstitial keratitis was developed by injecting live herpes simplex virus type 2 intrastromally into the corneas of presensitized rabbits. Herpes-infected corneas showed significantly more stromal infiltration and vascularization, iritis, conjunctivitis, and epithelial disease than the control corneas injected with cell supernatant without virus. Levels of total collagenase detected in the culture media of the herpes-infected corneas were high and were similar to those observed previously in alkali-burned rabbit corneas. Unlike alkali-burned corneas, the herpes-infected corneas showed much more of the enzyme in the latent form during the first two days of culture.

In a masked controlled study we compared 3% acycloguanosine, 0.5% idoxuridine, and 3% vidarabine ointments in therapy of experimental herpes simplex virus keratitis in rabbits. The results of the acycloguanosine group were significantly better than the control groups and both other treatment groups, while producing none of the toxic side effects of increasing iritis, conjunctivitis or stromal keratitis, with continued drug application.

Publisher Summary Silicon carbide (SiC) is perhaps the oldest semiconductor. Although in the last fifty years considerable use has been made of its abrasive properties, only in the past fifteen years has its potentialities as a semiconductor been exploited. The chapter discusses that Sic devices have distinct properties that lead to specific applications: they are operable up to 500oC, they have enhanced radiation resistance, and certain particular characteristics (example, band gap) lead to specific device applications. Applications in these areas determine the final utilization of Sic devices. The future development of Sic devices probably depends more on engineering perseverence than on semiconductor physics breakthrough.. The sophisticated active devices and integrated circuits now being prepared from silicon will be prepared from Sic when suitable crystals are available and the fabrication techniques are refined.

The metastable, ferromagnetic, tetragonal phase in the Mn-Al system has been obtained by isothermal transformation of a high-temperature phase. Transmission electron micrographs of specimens of this phase so obtained (bulk iHc = 1130 oe) show striations of light (transmitting) and dark (non-transmitting) material. The striations are presumed to arise from stresses induced by the transformation and/or cooling. Transmission electron diffractograms contain individual patterns both with and without superlattice reflections. Respective patterns reveal axial ratios of 0.90 and 0.94, and are correlated with the dark and light areas of the micrographs. From diffraction data it is concluded that the trace of the boundary between the light and dark regions coincides with a projection of the c axis. The possibility of coherency as a mechanism for the high coercive force, analogous to CoPt, is discussed. The type of cooperative atomic interaction as related to the shift in the axial ratio is also discussed.

• The present, masked, controlled study compares the therapeutic efficacy of guttate 3% vidarabine, 0.1% idoxuridine, and 1% trifluridine in herpes simplex keratouveitis in rabbits. Vidarabine, whether given every hour, every two hours, or every three hours was significantly better than controls but significantly worse than idoxuridine or trifluridine. Trifluridine and idoxuridine were not significantly different from each other. Viral cultures taken at the end of the six-day treatment period were positive in the majority of all treatment groups except for the trifluridine group, which was 100% negative. Although previous studies have shown that vidarabine is very effective as an antiviral ointment, vidarabine drops are not as effective as guttate idoxuridine or trifluridine.

The dynamics of open economy models embodying the assumption of perfect foresight have attracted a great deal of attention in the literature over recent years. A familiar conclusion to emerge from earlier analyses of dynamic monetary models under perfect foresight is that these models typically exhibit saddlepoint instability (see, for example, Burmeister and Dobell [1970], Nagatani [1970], Black [1974]). One approach around this instability problem, introduced by Sargent and Wallace [1973], is to assume that following any exogenous shock the system would jump to a stable path which converges to the new equilibrium. This procedure has been adopted by a number of authors (for example, Dornbusch [1976], Gray and Turnovsky [1979], Dornbusch and Fischer [1980], and Burmeister, Flood and Turnovsky [1981]).2 An implication of the jump is that at the point in time in which it occurs the assumption of perfect myopic foresight does not hold. However, as Gray and Turnovsky [1979] argued, this can be justified on the grounds that when a given shock is completely unanticipated it seems excessively stringent to require that expectations be perfectly accurate at the instant that the shock impinges on the system. Similar justification can be made in the case of pre-announced or anticipated policy changes as considered by Wilson [1979], Boyer and Hodrick [1982], as well as Gray and Turnovsky [1979]. In this case, the initial jump occurs at the time of announcement and the system remains on a continuous new equilibrium path at the time of policy implementation. Further, empirical evidence provides some support for the assumption that a system embodying the rational expectations hypothesis (or its deterministic analogue, perfect myopic foresight) will not arch away from the new equilibrium along a divergent path (see Flood and Garber [1980]). This paper deals with an economy operating under a flexible exchange rate and with perfect myopic foresight in expectations of the inflation rate and the rate of