bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical Models for Social Networks
Authors: Snijders Tom A.B.
Published: March 2011

Statistical models for social networks as dependent variables must represent the typical network dependencies between tie variables such as reciprocity, homophily, transitivity, etc. This review first treats models for single (cross-sectionally observed) networks and then for network dynamics. For single networks, the older literature concentrated on conditionally uniform models. Various types of latent space models have been developed: for discrete, general metric, ultrametric, Euclidean, and partially ordered spaces. Exponential random graph models were proposed long ago but now are applied more and more thanks to the non-Markovian social circuit specifications that were recently proposed. Modeling network dynamics is less complicated than modeling single network observations because dependencies are spread out in time. For modeling network dynamics, continuous-time models are more fruitful. Actor-oriented models here provide a model that can represent many dependencies in a flexible way. Strong model development is now going on to combine the features of these models and to extend them to more complicated outcome spaces.
Transpassive Dissolution of Copper and Rapid Formation of Brilliant Colored Copper Oxide Films
Authors: Fredj N. , Burleigh T. D.
Published: March 2011

This paper describes an electrochemical technique for growing adhesive copper oxide films on copper with attractive colors ranging from gold-brown to pearl with intermediate colors from red violet to gold green. The technique consists of anodically dissolving copper at transpassive potentials in hot sodium hydroxide, and then depositing brilliant color films of Cu2O onto the surface of copper after the anodic potential has been turned off. The color of the copper oxide film depends on the temperature, the anodic potential, the time t1 of polarization, and the time t2, which is the time of immersion after potential has been turned off. (At potentials lower than the transpassive region, that is, in the passive region, the oxide film is a dark gray or dark green matte with a blue powder hydroxide on the surface and it is not attractive.) The brilliant colored films were characterized using glancing angle x-ray diffraction, and the film was found to be primarily Cu2O. Cyclic voltammetry, chronopotentiometry, scanning electron microscopy, and x-ray photoelectron spectroscopy were also used to characterize these films. These techniques show that the different colors were due to differences in porosity and thickness rather than changes in composition.
Rhein ameliorates fatty liver disease through negative energy balance, hepatic lipogenic regulation, and immunomodulation in diet-induced obese mice
Authors: Sheng Xiaoyan , Wang Min , Lu Meng , Xi Beili , Sheng Hongguang , Zang Ying Qin
Published: March 2011

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and inflammatory disorders. In this study, we tested the effect of rhein, a lipophilic anthraquinone derived from a traditional Chinese herbal medicine Rheum palmatum L., on NAFLD-associated hepatic steatosis, insulin resistance, and the T helper (Th)1/Th2 cytokine imbalance in high-fat diet-induced obese (DIO) mice. We found that oral administration of rhein for 40 days significantly increased energy expenditure, reduced body weight, particularly body fat content, improved insulin resistance, and lowered circulating cholesterol levels in DIO mice without affecting food intake. Rhein treatment also reduced liver triglyceride levels, reversed hepatic steatosis, and normalized alanine aminotransferase (ALT) levels in these mice. Gene analysis and Western blot showed that rhein markedly suppressed the expression of the lipogenic enzyme sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes in the liver. Luciferase reporter assay revealed that rhein suppressed the transcriptional activity of SREBP-1c through its upstream regulator, liver X receptor (LXR). This suggests that rhein exerts its effects by targeting LXR, which is also supported by its inability to reduce body weight in LXR knockout mice. Moreover, multiplex ELISA displayed a downregulated Th1 response after rhein treatment. Rhein shifted the Th1/Th2 responses by inhibiting T-box expressed in T-cells (T-bet) expression and enhancing GATA-binding protein-3 (GATA-3) expression through increased signal transducer and activator of transcription 6 (STAT6) phosphorylation. These data indicate that rhein ameliorated NAFLD and associated disorders through LXR-mediated negative energy balance, metabolic regulatory pathways, and immunomodulatory activities involved in hepatic steatosis. The combined effects of rhein to target hepatic metabolic and immune pathways may be beneficial for complex metabolic diseases such as NAFLD.
Intestinal transit of a glucose bolus and incretin kinetics: a mathematical model with application to the oral glucose tolerance test
Authors: Salinari Serenella , Bertuzzi Alessandro , Mingrone Geltrude
Published: March 2011

The rate of appearance (Ra) of exogenous glucose in plasma after glucose ingestion is presently measured by tracer techniques that cannot be used in standard clinical testing such as the oral glucose tolerance test (OGTT). We propose a mathematical model that represents in a simple way the gastric emptying, the transport of glucose along the intestinal tract, and its absorption from gut lumen into portal blood. The model gives the Ratime course in terms of parameters with a physiological counterpart and provides an expression for the release of incretin hormones as related to glucose transit into gut lumen. Glucose absorption was represented by assuming two components related to a proximal and a distal transporter. Model performance was evaluated by numerical simulations. The model was then validated by fitting OGTT glucose and GLP-1 data in healthy controls and type 2 diabetic patients, and useful information was obtained for the rate of gastric emptying, the rate of glucose absorption, the Raprofile, the insulin sensitivity, and the glucose effectiveness. Model-derived estimates of insulin sensitivity were well correlated ( r = 0.929 in controls and 0.886 in diabetic patients) to data obtained from the euglycemic hyperinsulinemic clamp. Although the proposed OGTT analysis requires the measurement of an additional hormone concentration (GLP-1), it appears to be a reasonable choice since it avoids complex and expensive techniques, such as isotopes for glucose Rameasurement and direct assessment of gastric emptying and intestinal transit, and gives additional correlated information, thus largely compensating for the extra expense.
AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes
Authors: Darrabie Marcus D. , Arciniegas Antonio Jose Luis , Mishra Rajashree , Bowles Dawn E. , Jacobs Danny O. , Santacruz Lucia
Published: March 2011

Profound alterations in myocellular creatine and phosphocreatine levels are observed during human heart failure. To maintain its intracellular creatine stores, cardiomyocytes depend upon a cell membrane creatine transporter whose regulation is not clearly understood. Creatine transport capacity in the intact heart is modulated by substrate availability, and it is reduced in the failing myocardium, likely adding to the energy imbalance that characterizes heart failure. AMPK, a key regulator of cellular energy homeostasis, acts by switching off energy-consuming pathways in favor of processes that generate energy. Our objective was to determine the effects of substrate availability and AMPK activation on creatine transport in cardiomyocytes. We studied creatine transport in rat neonatal cardiomyocytes and HL-1 cardiac cells expressing the human creatine transporter cultured in the presence of varying creatine concentrations and the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). Transport was enhanced in cardiomyocytes following incubation in creatine-depleted medium or AICAR. The changes in transport were due to alterations in Vmax that correlated with changes in total and cell surface creatine transporter protein content. Our results suggest a positive role for AMPK in creatine transport modulation for cardiomyocytes in culture.
High-fat diet offsets the long-lasting effects of running-wheel access on food intake and body weight in OLETF rats
Authors: Chao Pei-Ting , Terrillion Chantelle E. , Moran Timothy H. , Bi Sheng
Published: March 2011

We have previously demonstrated that running-wheel access normalizes the food intake and body weight of Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Following 6 wk of running-wheel access beginning at 8 wk of age, the body weight of OLETF rats remains reduced, demonstrating a lasting effect on their phenotype. In contrast, access to a high-fat diet exacerbates the hyperphagia and obesity of OLETF rats. To determine whether diet modulates the long-term effects of exercise, we examined the effects of high-fat diet on food intake and body weight in OLETF rats that had prior access to running wheels for 4 wk. We found that 4 wk of running exercise significantly decreased food intake and body weight of OLETF rats. Consistent with prior results, 4 wk of exercise also produced long-lasting effects on food intake and body weight in OLETF rats fed a regular chow. When running wheels were relocked, OLETF rats stabilized at lower levels of body weight than sedentary OLETF rats. However, access to a high-fat diet offset these effects. When OLETF rats were switched to a high-fat diet following wheel relocking, they significantly increased food intake and body weight, so that they reached levels similar to those of sedentary OLETF rats fed a high-fat diet. Gene expression determination of hypothalamic neuropeptides revealed changes that appeared to be appropriate responses to the effects of diet and running exercise. Together, these results demonstrate that high-fat diet modulates the long-lasting effects of exercise on food intake and body weight in OLETF rats.
Albumin-induced epithelial-mesenchymal transition and ER stress are regulated through a common ROS-c-Src kinase-mTOR pathway: effect of imatinib mesylate
Authors: Lee Ji Young , Chang Jai Won , Yang Won Seok , Kim Soon Bae , Park Su Kil , Park Jung Sik , Lee Sang Koo
Published: March 2011

The epithelial-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress induced by urinary protein, particularly albumin, play an important role in tubulointerstitial injury. However, signaling pathways regulating both albumin-induced EMT and ER stress are not precisely known. We postulated that reactive oxygen species (ROS), c-Src kinase, and mammalian target of rapamysin (mTOR) would act as upstream signaling molecules. We further examined the effect of imatinib mesylate on these processes. All experiments were performed using HK-2 cells, a human proximal tubular cell line. Protein and mRNA expression were measured by Western blot analysis and real-time PCR, respectively. Exposure of tubular cells to albumin (5 mg/ml) for up to 5 days induced EMT in a time-dependent manner, as shown by conversion to the spindle-like morphology, loss of E-cadherin protein, and upregulation of α-smooth muscle actin mRNA and protein. Albumin also induced ER stress as evidenced by phosphorylation of eukaryotic translation initiation factor-2α and increased expression of GRP78 mRNA and protein. Albumin induced ROS, c-Src kinase, and mTOR as well. Antioxidants, c-Src kinase inhibitor (PP2), and mTOR inhibitor (rapamycin) suppressed the albumin-induced EMT and ER stress. Antioxidants and PP2 inhibited the albumin-induced c-Src kinase and mTOR, respectively. Imatinib suppressed the albumin-induced EMT and ER stress via inhibition of ROS and c-Src kinase. Imatinib also inhibited the albumin-induced mRNA expression of MCP-1, VCAM-1, transforming growth factor (TGF)-β1, and collagen I (α1). In conclusion, the ROS-c-Src kinase-mTOR pathway played a central role in the signaling pathway that linked albumin to EMT and ER stress. Imatinib might be beneficial in attenuating the albumin-induced tubular injury.
Basolateral amygdala responds robustly to social calls: spiking characteristics of single unit activity
Authors: Naumann Robert T. , Kanwal Jagmeet S.
Published: March 2011

Vocalizations emitted within a social context can trigger call-specific changes in the emotional and physiological/autonomic state of the receiver. The amygdala is implicated in mediating these changes, but its role in call perception remains relatively unexplored. We examined call and pitch selectivity of single neurons within the basolateral amygdala (BLA) by recording spiking activity in response to 5 pitch variants of each of 14 species-specific calls presented to awake, head-restrained mustached bats, Pteronotus parnellii. A response-wise analysis across neurons revealed seven types of temporal response patterns based on the timing and duration of spiking. Roughly half of the responses to different call types were significantly affected by changes in call pitch. A neuron-wise analysis revealed that ∼12% (8/69) of the neurons preferred the same pitch across all call types. Ninety-three percent (93/100) of neurons were excited by at least one call type and 76% exhibited either complete or transient suppression to one or more call types. The majority of neurons preferred fewer than half of the 14 different simple-syllabic calls. A call-wise analysis of spiking activity revealed that call types signaling either threat or fear most consistently evoked increases in the spike rate. In contrast, calls emitted during appeasement tended to evoke spike suppression. Our data suggest that BLA neurons participate in the processing of multiple call types and exhibit a rich variety of temporal response patterns that are neither neuron nor call specific.
IUGR decreases elastin mRNA expression in the developing rat lung and alters elastin content and lung compliance in the mature rat lung
Authors: Joss-Moore Lisa A. , Wang Yan , Yu Xing , Campbell Michael S. , Callaway Christopher W. , McKnight Robert A. , Wint Albert , Dahl Mar Janna , Dull Randal O. , Albertine Kurt H. , Lane Robert H.
Published: March 2011

Complications of intrauterine growth restriction (IUGR) include increased pulmonary morbidities and impaired alveolar development. Normal alveolar development depends upon elastin expression and processing, as well as the formation and deposition of elastic fibers. This is true of the human and rat. In this study, we hypothesized that uteroplacental insufficiency (UPI)-induced IUGR decreases mRNA levels of elastin and genes required for elastin fiber synthesis and assembly, at birth (prealveolarization) and postnatal day 7 (midalveolarization) in the rat. We further hypothesized that this would be accompanied by reduced elastic fiber deposition and increased static compliance at postnatal day 21 (mature lung). We used a well characterized rat model of IUGR to test these hypotheses. IUGR decreases mRNA transcript levels of genes essential for elastic fiber formation, including elastin, at birth and day 7. In the day 21 lung, IUGR decreases elastic fiber deposition and increases static lung compliance. We conclude that IUGR decreases mRNA transcript levels of elastic fiber synthesis genes, before and during alveolarization leading to a reduced elastic fiber density and increased static lung compliance in the mature lung. We speculate that the mechanism by which IUGR predisposes to pulmonary disease may be via decreased lung elastic fiber deposition.
Syntheses and Crystal Structures of and
Authors: Fujii Takayoshi , Kanno Mihoko , Hirata Mitsuo
Published: March 2011

We have prepared the trinuclear complexes (3) and (4), from the reaction of with (1) and determined their structures by X-ray crystallographic analysis. In both complexes, two monoanions chelate the Cu(II) center in square-planar geometry, whereas the terminal Cu(II) center is four-coordinate and a distorted tetrahedron.
Determination of Chlorinity of Water without the Use of Chromate Indicator
Authors: Hong Tae-Kee , Kim Myung-Hoon , Czae Myung-Zoon
Published: March 2011

A new method for determining chlorinity of water was developed in order to improve the old method by alleviating the environmental problems associated with the toxic chromate. The method utilizes a mediator, a weak acid that can form an insoluble salt with the titrant. The mediator triggers a sudden change in pH at an equivalence point in a titration. Thus, the equivalence point can be determined either potentiometrically (using a pH meter) or simply with an acid-base indicator. Three nontoxic mediators (phosphate, EDTA, and sulfite) were tested, and optimal conditions for the sharpest pH changes were sought. A combination of phosphate (a mediator) and phenolphthalein (an indicator) was found to be the most successful. The choices of the initial pH and the concentration of the mediator are critical in this approach. The optimum concentration of the mediator isca.1~2 mM, and the optimum value of the initial pH isca.9 for phosphate/phenolphthalein system. The method was applied to a sample of sea water, and the results are compared with those from the conventional Mohr-Knudsen method. The new method yielded chlorinity of a sample of sea water of (17.58 ± 0.22) g/kg, which is about 2.5% higher than the value (17.12 ± 0.22) g/kg from the old method.
Primordial Non‐Gaussianity in the Large‐Scale Structure of the Universe
Authors: Desjacques Vincent , Seljak Uroš
Published: March 2011

Primordial non‐Gaussianity is a potentially powerful discriminant of the physical mechanisms that
generated the cosmological fluctuations observed today. Any detection of significant non‐Gaussianity would thus have profound implications for our understanding of cosmic structure formation. The large‐scale mass distribution in the Universe is a sensitive probe of the nature of initial conditions. Recent theoretical progress together with rapid developments in observational techniques will enable us to critically confront predictions of inflationary scenarios and set constraints as competitive as those from the Cosmic Microwave Background. In this paper, we review past and current efforts in the search for primordial non‐Gaussianity in the large‐scale structure of the Universe.
Temporary Workforce Planning with Firm Contracts: A Model and a Simulated Annealing Heuristic
Authors: Al-Salamah Muhammad
Published: March 2011

The aim of this paper is to introduce a model for temporary staffing when temporary employment is managed by firm contracts and to propose a simulated annealing‐based method to solve the model. Temporary employment is a policy frequently used to adjust the working hour capacity to fluctuating demand. Temporary workforce planning models have been unnecessarily simplified to account for only periodic hiring and laying off; a company can review its workforce requirement every period and make hire‐fire decisions accordingly, usually with a layoff cost. We present a more realistic temporary workforce planning model that assumes a firm contract between the worker and the company, which can extend to several periods. The model assumes the traditional constraints, such as inventory balance constraints, worker availability, and labor hour mix. The costs are the inventory holding cost, training cost of the temporary workers, and the backorder cost. The mixed integer model developed for this case has been found to be difficult to solve even for small problem sizes; therefore, a simulated annealing algorithm is proposed to solve the mixed integer model. The performance of the SA algorithm is compared with the CPLEX solution.
Effects of Salvianolic Acid B on Protein Expression in Human Umbilical Vein Endothelial Cells
Authors: Chang Tsong-Min , Shi Guey-Yueh , Wu Hua-Lin , Wu Chieh-Hsi , Su Yan-Di , Wang Hui-Lin , Wen Hsin-Yun , Huang Huey-Chun
Published: March 2011

Salvianolic acid B (Sal B), a pure water‐soluble compound extracted from Radix Salviae miltiorrhizae, has been reported to possess potential cardioprotective efficacy. To identify proteins or pathways by which Sal B might exert its protective activities on the cardiovascular system, two‐dimensional gel electrophoresis‐based comparative proteomics was performed, and proteins altered in their expression level after Sal B treatment were identified by MALDI‐TOF MS/MS. Human umbilical vein endothelial cells (HUVECs) were incubated at Sal B concentrations that can be reached in human plasma by pharmacological intervention. Results indicated that caldesmon, an actin‐stabilizing protein, was downregulated in Sal B‐exposed HUVECs. Proteins that showed increased expression levels upon Sal B treatment were vimentin, T‐complex protein 1, protein disulfide isomerase, tropomyosin alpha, heat shock protein beta‐1, UBX domain‐containing protein 1, alpha enolase, and peroxiredoxin‐2. Additionally, Sal B leads to increased phosphorylation of nucleophosmin in a dose‐dependent manner and promotes proliferation of HUVECs. We found that Sal B exhibited a coordinated regulation of enzymes and proteins involved in cytoskeletal reorganization, oxidative stress, and cell growth. Our investigation would provide understanding to the endothelium protection information of Sal B.
Dynamic Reconfigurable Computing: The Alternative to Homogeneous Multicores under Massive Defect Rates
Authors: Magalhães Pereira Monica , Carro Luigi
Published: March 2011

The aggressive scaling of CMOS technology has increased the density and allowed the integration of multiple processors into a single chip. Although solutions based on MPSoC architectures can increase application's speed through TLP exploitation, this speedup is still limited to the amount of parallelism available in the application, as demonstrated by Amdahl's Law. Moreover, with the continuous shrinking of device features, very aggressive defect rates are expected for new technologies. Under high defect rates a large amount of processors of the MPSoC will be susceptible to defects and consequently will fail, not only reducing yield but also severely affecting the expected performance. This paper presents a run-time adaptive architecture that allows software execution even under aggressive defect rates. The proposed architecture can accelerate not only highly parallel applications but also sequential ones, and it is a heterogeneous solution to overcome the performance penalty that is imposed to homogeneous MPSoCs under massive defect rates.
Long-Term Variability and Trends in the Caribbean Sea
Authors: Jury Mark R.
Published: March 2011

Upper ocean conditions in the Caribbean Sea are studied for long-term variability and trends using filtered surface observations and ocean model reanalysis fields. A principal component analysis is made, and trends in the leading mode are extracted. Sea surface temperature shows an accelerating upward trend while air pressure exhibits quasidecadal fluctuations. Sea surface height and subsurface temperature rise linearly while subsurface salinity exhibits fresher upper and saltier lower layers. The amplitude of warming is highest in the southern Caribbean east of 75°W near 150 m and lowest near the surface, indicating little role for a top-down process such as air-sea exchange. The freshening surface layer does not appear connected to river discharge or regional rainfall, so changes in ocean advection and sources are the likely drivers. Westward currents exhibit a reduction of throughflow and an influx from the Windward Passage. The Caribbean Current has slowed ~0.06 m/s in the reanalysis era. Crop yields show little sensitivity to ocean conditions but tend to follow rainfall. Marine catch per capita in the Caribbean follows subsurface currents and vertical motion but is less affected by temperature and salinity.
Hepatoportal Leptin Sensors and Their Reflex Effects on Autonomic Outflow in the Rat
Authors: Niijima Akira
Published: March 2011

Afferent nerve signals were recorded from a peripheral cut end of the small nerve bundle of the hepatic branch of the vagus nerve in anesthetized rats. An injection of leptin (100 pg, 0.1 mL) into the portal vein facilitated the afferent activity. The response was dose dependent. Further, an intravenous (IV) injection of leptin (1 ng, 0.1 mL) facilitated the efferent nerve activity of the sympathetic nerve to the adrenal gland and suppressed that of the celiac branch of the vagus nerve. In hepatic vagotomized rats, no change in efferent activity of the adrenal sympathetic nerve nor celiac branch of the vagus nerve was observed following iv administration of leptin. These observations suggest that leptin sensors in the hepatoportal region play a role in reflex modulation of autonomic outflow in relation to metabolic functions.
The Problem of Metal Needles in Acupuncture‐fMRI Studies
Authors: Beissner Florian , Nöth Ulrike , Schockert Thomas
Published: March 2011

Acupuncture is a therapy based on sensory stimulation of the human
body by means of metal needles. The exact underlying mechanisms of
acupuncture have not been clarified so far. Functional magnetic
resonance imaging (fMRI) has become an important tool in
acupuncture research. Standard acupuncture needles, which are made
of ferromagnetic steel, however, are problematic in
acupuncture‐fMRI studies for several reasons, such as attraction
by the scanner′s magnetic field, significant image distortions and
signal‐dropouts, when positioned close to the head or even heating
due to absorption of radio frequency (RF). The aim of this study
was to compare two novel types of acupuncture needles with a
standard needle for their effect on MRI image quality. The
standard needle severely reduced image quality, when located
inside the RF coil. The nonferromagnetic metal needle may pose a
risk due to RF heating, while the plastic needle has a
significantly larger diameter. In conclusion, our recommendations
are: (1) standard needles should not be used in MRI; (2)
Nonferromagnetic metal needles seem to be the best choice for
acupoints outside of the transmitter coil; and (3) only plastic
needles are suited for points inside the coil. Laser acupuncture
may be a safe alternative, too.
Novel Diagnostic Algorithm for the Floating and Sunken Pulse Qualities and Its Clinical Test
Authors: Kim Jaeuk U. , Jeon Young Ju , Lee Yu Jung , Kim Keun Ho , Kim Jong Yeol
Published: March 2011

We propose a novel classification algorithm for the floating pulse and the sunken pulse using a newly defined coefficient (Cfs). To examine the validity of the proposed algorithm, we carried out a clinical test in which 12 oriental medical doctors made pairwise diagnoses on the pulses of volunteering subjects. 169 subjects were simultaneously diagnosed by paired doctors, and the diagnoses in 121 subjects were concordant, yielding an accuracy of 72% and a Matthews correlation coefficient of 0.42, which indicates reasonable agreement between doctors. Two sample T‐tests showed that subjects in the sunken pulse group had significantly higher BMI and Cfs (P < .05) than those in the floating pulse group. The pulse classification by the algorithm converged with the diagnoses of paired doctors with an accuracy up to 69%. With these results, we confirm the validity of the novel classification algorithm for the floating and sunken pulses.
Antibody-Based Therapies in Multiple Myeloma
Authors: Tai Yu-Tzu , Anderson Kenneth C.
Published: March 2011

The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies have largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA) approval of therapeutic Abs for cancer and other diseases.
Mathematical Modeling Predicts Synergistic Antitumor Effects of Combining a Macrophage-Based, Hypoxia-Targeted Gene Therapy with Chemotherapy
Authors: Owen Markus R. , Stamper I. Johanna , Muthana Munitta , Richardson Giles W. , Dobson Jon , Lewis Claire E. , Byrne Helen M.
Published: March 2011

Tumor hypoxia is associated with low rates of cell proliferation and poor drug delivery, limiting the efficacy of many conventional therapies such as chemotherapy. Because many macrophages accumulate in hypoxic regions of tumors, one way to target tumor cells in these regions could be to use genetically engineered macrophages that express therapeutic genes when exposed to hypoxia. Systemic delivery of such therapeutic macrophages may also be enhanced by preloading them with nanomagnets and applying a magnetic field to the tumor site. Here, we use a new mathematical model to compare the effects of conventional cyclophosphamide therapy with those induced when macrophages are used to deliver hypoxia-inducible cytochrome P450 to locally activate cyclophosphamide. Our mathematical model describes the spatiotemporal dynamics of vascular tumor growth and treats cells as distinct entities. Model simulations predict that combining conventional and macrophage-based therapies would be synergistic, producing greater antitumor effects than the additive effects of each form of therapy. We find that timing is crucial in this combined approach with efficacy being greatest when the macrophage-based, hypoxia-targeted therapy is administered shortly before or concurrently with chemotherapy. Last, we show that therapy with genetically engineered macrophages is markedly enhanced by using the magnetic approach described above, and that this enhancement depends mainly on the strength of the applied field, rather than its direction. This insight may be important in the treatment of nonsuperficial tumors, where generating a specific orientation of a magnetic field may prove difficult. In conclusion, we demonstrate that mathematical modeling can be used to design and maximize the efficacy of combined therapeutic approaches in cancer. Cancer Res; 71(8); 2826–37. ©2011 AACR.
Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer
Authors: Morgan Richard , Boxall Angela , Bhatt Aagna , Bailey Michael , Hindley Richard , Langley Stephen , Whitaker Hayley C. , Neal David E. , Ismail Mohammed , Whitaker Hamish , Annels Nicola , Michael Agnieszka , Pandha Hardev
Published: March 2011

Purpose: Prostate cancer (PC) is the second most common cause of cancer related death in men. A number of key limitations with prostate specific antigen (PSA), currently the standard detection test, has justified evaluation of new biomarkers. We have assessed the diagnostic potential of Engrailed-2 (EN2) protein, a homeodomain-containing transcription factor expressed in PC cell lines and secreted into the urine by PC in men.

Experimental Design: EN2 expression in PC cell lines and prostate cancer tissue was determined by semi-quantative RT-PCR and immunohistochemistry. First pass urine [without prior digital rectal examination (DRE)] was collected from men presenting with urinary symptoms (referred to exclude/confirm the presence of prostate cancer) and from controls. EN2 protein was measured by ELISA in urine from men with PC (n = 82) and controls (n = 102).

Results: EN2 was expressed and secreted by PC cell lines and PC tissue but not by normal prostate tissue or stroma. The presence of EN2 in urine was highly predictive of PC, with a sensitivity of 66% and a specificity of 88.2%, without requirement for DRE. There was no correlation with PSA levels. These results were confirmed independently by a second academic center.

Conclusions: Urinary EN2 is a highly specific and sensitive candidate biomarker of prostate cancer. A larger multicenter study to further evaluate the diagnostic potential of EN2 is justified. Clin Cancer Res; 17(5); 1090–8. ©2011 AACR.
Changes in 18F-Fluorodeoxyglucose and 18F-Fluorodeoxythymidine Positron Emission Tomography Imaging in Patients with Non–Small Cell Lung Cancer Treated with Erlotinib
Authors: Mileshkin Linda , Hicks Rodney J. , Hughes Brett G.M. , Mitchell Paul L.R. , Charu Veena , Gitlitz Barbara J. , Macfarlane David , Solomon Benjamin , Amler Lukas C. , Yu Wei , Pirzkall Andrea , Fine Bernard M.
Published: March 2011

Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non–small-cell lung cancer patients treated with erlotinib.

Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤5 lesions/patient) of 15% or more maximum standardized uptake value. PFS was investigator-determined.

Results: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56; 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT; all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue; all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS; HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders.

Conclusion: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects. Clin Cancer Res; 17(10); 3304–15. ©2011 AACR.
A Human Model of Epithelial to Mesenchymal Transition to Monitor Drug Efficacy in Hepatocellular Carcinoma Progression
Authors: van Zijl Franziska , Mall Sabine , Machat Georg , Pirker Christine , Zeillinger Robert , Weinhaeusel Andreas , Bilban Martin , Berger Walter , Mikulits Wolfgang
Published: March 2011

The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation. Therapeutic agents clinically used against HCC were examined for efficacy by determination of IC50 values. We show that liver cancer cell lines exhibited either an epithelial or mesenchymal phenotype of which the latter showed strong migratory and invasive abilities in vitro. The common cellular origin of both cell types indicated that mesenchymal HCC cells have been derived from epithelial hepatocytes through EMT in the HCC patient. Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells, which were slightly more resistant to cytostatic drugs. Most remarkably, combined treatment with doxorubicin and sorafenib caused increased susceptibility of both HCC cell types resulting in enhanced drug efficacy. Taken together, this EMT model of human HCC allows the identification of molecular mechanisms and the assessment of therapeutic drug efficacy during liver cancer progression in preclinical studies. Mol Cancer Ther; 10(5); 850–60. ©2011 AACR.
hTERT Promotes Imatinib Resistance in Chronic Myeloid Leukemia Cells: Therapeutic Implications
Authors: Deville Laure , Hillion Josette , Pendino Frédéric , Samy Mona , Nguyen Eric , Ségal-Bendirdjian Evelyne
Published: March 2011

Imatinib mesylate has shown remarkable efficacy in the treatment of patients in the chronic phase of chronic myeloid leukemia. However, despite an overall significant hematological and cytogenetic response, imatinib therapy may favor the emergence of drug-resistant clones, ultimately leading to relapse. Some imatinib resistance mechanisms had not been fully elucidated yet. In this study we used sensitive and resistant sublines from a Bcr-Abl positive cell line to investigate the putative involvement of telomerase in the promotion of imatinib resistance. We showed that sensitivity to imatinib can be partly restored in imatinib-resistant cells by targeting telomerase expression, either by the introduction of a dominant-negative form of the catalytic protein subunit of the telomerase (hTERT) or by the treatment with all-trans-retinoic acid, a clinically used drug. Furthermore, we showed that hTERT overexpression favors the development of imatinib resistance through both its antiapoptotic and telomere maintenance functions. Therefore, combining antitelomerase strategies to imatinib treatment at the beginning of the treatment should be promoted to reduce the risk of imatinib resistance development and increase the probability of eradicating the disease. Mol Cancer Ther; 10(5); 711–19. ©2011 AACR.
HIF-1–Dependent Stromal Adaptation to Ischemia Mediates In Vivo Tumor Radiation Resistance
Authors: Schwartz David L. , Bankson James , Bidaut Luc , He Yi , Williams Ryan , Lemos Robert , Thitai Arun Kumar , Oh Junghwan , Volgin Andrei , Soghomonyan Suren , Yeh Hsin-Hsien , Nishii Ryuichi , Mukhopadhay Uday , Alauddin Mian , Mushkudiani Ioseb , Kuno Norihito , Krishnan Sunil , Bornman William , Lai Stephen Y. , Powis Garth , Hazle John , Gelovani Juri
Published: March 2011

Purpose: Hypoxia-inducible factor 1 (HIF-1) promotes cancer cell survival and tumor progression. The specific role played by HIF-1 and tumor–stromal interactions toward determining tumor resistance to radiation treatment remains undefined. We applied a multimodality preclinical imaging platform to mechanistically characterize tumor response to radiation, with a focus on HIF-1–dependent resistance pathways.

Methods: C6 glioma and HN5 human squamous carcinoma cells were stably transfected with a dual HIF-1 signaling reporter construct (dxHRE-tk/eGFP-cmvRed2XPRT). Reporter cells were serially interrogated in vitro before and after irradiation as monolayer and multicellular spheroid cultures and as subcutaneous xenografts in nu/nu mice.

Results: In vitro, single-dose irradiation of C6 and HN5 reporter cells modestly impacted HIF-1 signaling in normoxic monolayers and inhibited HIF-1 signaling in maturing spheroids. In contrast, irradiation of C6 or HN5 reporter xenografts with 8 Gy in vivo elicited marked upregulation of HIF-1 signaling and downstream proangiogenic signaling at 48 hours which preceded recovery of tumor growth. In situ ultrasound imaging and dynamic contrast-enhanced (DCE) MRI indicated that HIF-1 signaling followed acute disruption of stromal vascular function. High-resolution positron emission tomography and dual-contrast DCE-MRI of immobilized dorsal skin window tumors confirmed postradiotherapy HIF-1 signaling to spatiotemporally coincide with impaired stromal vascular function. Targeted disruption of HIF-1 signaling established this pathway to be a determinant of tumor radioresistance.

Conclusions: Our results illustrate that tumor radioresistance is mediated by a capacity to compensate for stromal vascular disruption through HIF-1–dependent proangiogenic signaling and that clinically relevant vascular imaging techniques can spatially define mechanisms associated with tumor irradiation. Mol Cancer Res; 9(3); 259–70. ©2011 AACR.
STAT-3 Activates NF-κB in Chronic Lymphocytic Leukemia Cells
Authors: Liu Zhiming , Hazan-Halevy Inbal , Harris David M. , Li Ping , Ferrajoli Alessandra , Faderl Stefan , Keating Michael J. , Estrov Zeev
Published: March 2011

NF-κB plays a major role in the pathogenesis of B-cell neoplasms. A broad array of mostly extracellular stimuli has been reported to activate NF-κB, to various degrees, in chronic lymphocytic leukemia (CLL) cells. Because CLL cells harbor high levels of unphosphorylated STAT-3 (USTAT-3) and USTAT-3 was reported to activate NF-κB, we sought to determine whether USTAT-3 activates NF-κB in CLL. Using the electrophoretic mobility shift assay (EMSA), we studied peripheral blood low-density cells from 15 patients with CLL and found that CLL cell nuclear extracts from all the samples bound to an NF-κB DNA probe, suggesting that NF-κB is constitutively activated in CLL. Immunoprecipitation studies showed that STAT-3 bound NF-κB p65, and confocal microscopy studies detected USTAT-3/NF-κB complexes in the nuclei of CLL cells, thereby confirming these findings. Furthermore, infection of CLL cells with retroviral STAT-3-short hairpin RNA attenuated the binding of NF-κB to DNA, as assessed by EMSA, and downregulated mRNA levels of NF-κB–regulated genes, as assessed by quantitative PCR. Taken together, our data suggest that USTAT-3 binds to the NF-κB p50/p65 dimers and that the USTAT-3/NF-κB complexes bind to DNA and activate NF-κB–regulated genes in CLL cells. Mol Cancer Res; 9(4); 507–15. ©2011 AACR.
Renaissance of Brown Adipose Tissue
Authors: Tews D. , Wabitsch M.
Published: March 2011

The recent discovery of functional brown adipose tissue in human adults raised this tissue again into the focus of current investigations concerning human energy homeostasis. Brown fat is a key thermogenic tissue and is essential for non-shivering thermogenesis in the human newborn and hibernating mammals. This review highlights the biological and molecular aspects of brown adipose tissue development and function from the embryonic state to childhood and adolescence.
Paclitaxel-Eluting Stents Compared With Bare Metal Stents in Diabetic Patients With Acute Myocardial Infarction
Authors: Witzenbichler Bernhard , Wöhrle Jochen , Guagliumi Giulio , Peruga Jan Z. , Brodie Bruce R. , Dudek Dariusz , Kornowski Ran , Hartmann Franz , Hood Kristin L. , Parise Helen , Lansky Alexandra J. , Nikolsky Eugenia , Mehran Roxana , Stone Gregg W.
Published: March 2011

Background—

In the prospective, randomized Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, implantation of paclitaxel-eluting stents (PES) safely reduced the rates of ischemic target lesion revascularization (TLR) compared with bare metal stents (BMS) in patients with ST-segment–elevation myocardial infarction (STEMI) undergoing primary percutaneous intervention. Diabetes mellitus is a known predictor of adverse outcomes after percutaneous intervention in STEMI. We therefore sought to assess the impact of PES in diabetic patients with STEMI from the HORIZONS-AMI trial.

Methods and Results—

A total of 478 patients with diabetes and 2527 without diabetes were randomly assigned to receive PES versus BMS. The 12-month rates of ischemic TLR were significantly reduced by PES compared with BMS in both diabetic (11.2% versus 5.2%; hazard ratio [95% confidence interval]=0.45 [0.21 to 0.93];
P
=0.03) and nondiabetic (6.8% versus 4.3%, hazard ratio [95% confidence interval]=0.63 [0.44 to 0.92];
P
=0.02) patients. In patients with insulin-treated diabetes, PES compared with BMS reduced the 12-month TLR rate from 21.4% to 7.3% (hazard ratio [95% confidence interval]=0.35 [0.12 to 1.03];
P
=0.046). Angiographic late loss and binary restenosis at 13 months were also significantly reduced in PES-treated diabetic patients. There were no significant differences between the BMS and PES groups in the 12-month rates of death, reinfarction, stroke, or stent thrombosis in either diabetic or nondiabetic patients.

Conclusions—

In the large-scale, prospective, randomized HORIZONS-AMI trial, implantation of PES compared with BMS in patients with STEMI and diabetes mellitus resulted in significant reductions in ischemia-driven TLR and angiographic restenosis at 1 year, with comparable safety outcomes, including stent thrombosis. These results suggest that PES can safely be used to reduce restenosis in high-risk diabetic patients presenting with STEMI.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00433966.
Gender Bias in Studies for Food and Drug Administration Premarket Approval of Cardiovascular Devices
Authors: Dhruva Sanket S. , Bero Lisa A. , Redberg Rita F.
Published: March 2011

Background—

Cardiovascular devices can have different safety and effectiveness profiles in men and women. The type and quality of sex-specific data reviewed by the Food and Drug Administration (FDA) before approval of these devices are unknown.

Methods and Results—

We performed a systematic review of the demographics, comments on gender bias, and analysis of results by sex for 78 high-risk cardiovascular devices that received premarket approval by the FDA between 2000 and 2007. FDA summaries of evidence did not report sex of enrollees in 34 (28%) of 123 studies. For studies reporting sex distribution, the study populations were, on average, 67% men. There was no increase in the enrollment of women over time. Explanations for the relatively low percentage of women often stated that the trials reflected either underlying disease distribution or referral rates for similar procedures or that the sex distribution reflected similar or previous trials. Forty-one percent of studies included a gender bias comment or analysis, and 12 (26%) of 47 of these analyses identified some difference in device safety or effectiveness by sex.

Conclusions—

There is a lack of sex-specific safety and effectiveness data for high-risk cardiovascular devices before FDA approval. The justifications for this lack of evidence may perpetuate the status quo. More rigorous FDA requirements for sex-specific data before device approval could present an opportunity to improve cardiovascular outcomes.
Radar and weather
Authors: Wexler Raymond , Swingle Donald M.
Published: March 2011

No Abstract Available
Reply
Authors: Maynard R. H.
Published: March 2011

No Abstract Available