CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit the access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA tumor microenvironment promote concomitant chemotherapy delivery and increased antineoplastic response in murine models of PDA. Prior studies could not determine whether chemotherapy delivery or microenvironment modulation per se were the dominant features in treatment response, and such information could guide the optimal translation of these preclinical findings to patients. To distinguish between these possibilities, we used a chemical inhibitor of cytidine deaminase to stabilize and thereby artificially elevate gemcitabine levels in murine PDA tumors without disrupting the tumor microenvironment. Additionally, we used the FG-3019 monoclonal antibody (mAb) that is directed against the pleiotropic matricellular signaling protein connective tissue growth factor (CTGF/CCN2). Inhibition of cytidine deaminase raised the levels of activated gemcitabine within PDA tumors without stimulating neoplastic cell killing or decreasing the growth of tumors, whereas FG-3019 increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. The response to FG-3019 correlated with the decreased expression of a previously described promoter of PDA chemotherapy resistance, the X-linked inhibitor of apoptosis protein. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models, and by extension in PDA patients

Recent magnetic views of the Antarctic lithosphere

Magnetic anomaly investigations are a key tool to help unveil subglacial geology, crustal architecture and the tectonic and geodynamic evolution of the Antarctic continent. Here, we present the second generation Antarctic magnetic anomaly compilation ADMAP 2.0 (Golynsky et al., 2018), that now includes a staggering 3.5 million line-km of aeromagnetic and marine magnetic data, more than double the amount of data available in the first generation effort. All the magnetic data were corrected for the International Geomagnetic Reference Field, diurnal effects, high-frequency errors and leveled, gridded,and stitched together. The new magnetic anomaly dataset provides tantalising new views into the structure and evolution of the Antarctic Peninsula and the West Antarctic Rift System within West Antarctica, and Dronning Maud Land, the Gamburtsev Subglacial Mountains, the Prince Charles Mountains, Princess Elizabeth Land, and Wilkes Land in East Antarctica, as well as key insights into oceanic gateways. Our magnetic anomaly compilation is helping unify disparate regional geologic and geophysical studies by providing larger-scale perspectives into the major tectonic and magmatic processes that affected Antarctica from Precambrian to Cenozoic times, including e.g. the processes of subduction and magmatic arc development, orogenesis, accretion, cratonisation and continental rifting, as well as continental margin and oceanic basin evolution. The international Antarctic geomagnetic community remains very active in the wake of ADMAP 2.0, and we will showcase some of their key ongoing study areas, such as the South Pole and Recovery frontiers, the Ross Ice Shelf, Dronning Maud Land and Princess Elizabeth Land

Making things happen : a model of proactive motivation

Being proactive is about making things happen, anticipating and preventing problems, and seizing opportunities. It involves self-initiated efforts to bring about change in the work environment and/or oneself to achieve a different future. The authors develop existing perspectives on this topic by identifying proactivity as a goal-driven process involving both the setting of a proactive goal (proactive goal generation) and striving to achieve that proactive goal (proactive goal striving). The authors identify a range of proactive goals that individuals can pursue in organizations. These vary on two dimensions: the future they aim to bring about (achieving a better personal fit within one’s work environment, improving the organization’s internal functioning, or enhancing the organization’s strategic fit with its environment) and whether the self or situation is being changed. The authors then identify “can do,” “reason to,” and “energized to” motivational states that prompt proactive goal generation and sustain goal striving. Can do motivation arises from perceptions of self-efficacy, control, and (low) cost. Reason to motivation relates to why someone is proactive, including reasons flowing from intrinsic, integrated, and identified motivation. Energized to motivation refers to activated positive affective states that prompt proactive goal processes. The authors suggest more distal antecedents, including individual differences (e.g., personality, values, knowledge and ability) as well as contextual variations in leadership, work design, and interpersonal climate, that influence the proactive motivational states and thereby boost or inhibit proactive goal processes. Finally, the authors summarize priorities for future researc

Optical dipole traps and atomic waveguides based on Bessel light beams

We theoretically investigate the use of Bessel light beams generated using axicons for creating optical dipole traps for cold atoms and atomic waveguiding. Zeroth-order Bessel beams can be used to produce highly elongated dipole traps allowing for the study of one-dimensional trapped gases and realization of a Tonks gas of impentrable bosons. First-order Bessel beams are shown to be able to produce tight confined atomic waveguides over centimeter distances.Comment: 20 pages, 5 figures, to appear in Phys. Rev.

Quantum computing in optical microtraps based on the motional states of neutral atoms

We investigate quantum computation with neutral atoms in optical microtraps where the qubit is implemented in the motional states of the atoms, i.e., in the two lowest vibrational states of each trap. The quantum gate operation is performed by adiabatically approaching two traps and allowing tunneling and cold collisions to take place. We demonstrate the capability of this scheme to realize a square-root of swap gate, and address the problem of double occupation and excitation to other unwanted states. We expand the two-particle wavefunction in an orthonormal basis and analyze quantum correlations throughout the whole gate process. Fidelity of the gate operation is evaluated as a function of the degree of adiabaticity in moving the traps. Simulations are based on rubidium atoms in state-of-the-art optical microtraps with quantum gate realizations in the few tens of milliseconds duration range.Comment: 11 pages, 7 figures, for animations of the gate operation, see http://www.itp.uni-hannover.de/~eckert/na/index.htm

Theoretical Directional and Modulated Rates for Direct SUSY Dark Matter Detection

Exotic dark matter together with the vacuum energy (cosmological constant) seem to dominate in the flat Universe. Thus direct dark matter detection is central to particle physics and cosmology. Supersymmetry provides a natural dark matter candidate, the lightest supersymmetric particle (LSP). Furthermore from the knowledge of the density and velocity distribution of the LSP, the quark substructure of the nucleon and the nuclear structure (form factor and/or spin response function), one is able to evaluate the event rate for LSP-nucleus elastic scattering. The thus obtained event rates are, however, very low. So it is imperative to exploit the two signatures of the reaction, namely the modulation effect, i.e. the dependence of the event rate on the Earth's motion, and the directional asymmetry, i.e. the dependence of the rate on the the relative angle between the direction of the recoiling nucleus and the sun's velocity. These two signatures are studied in this paper employing various velocity distributions and a supersymmetric model with universal boundary conditions at large tan(beta).Comment: 11 LATEX pages, 1 table and 4 ps figures included. Paper presented in DARK2002, Fourth Heidelberg International Conference on Dark Matter in Astro- and Particle Physics, Cape Town, South Africa, 4-9 February, 2002, to appear in the proceedings (to be published by Springer Verlag

Proto-oncogene HER-2 in normal, dysplastic and tumorous feline mammary glands: an immunohistochemical and chromogenic in situ hybridization study

<p>Abstract</p> <p>Background</p> <p>Feline mammary carcinoma has been proposed as a natural model of highly aggressive, hormone-independent human breast cancer. To further explore the utility of the model by adding new similarities between the two diseases, we have analyzed the oncogene HER-2 status at both the protein and the gene levels.</p> <p>Methods</p> <p>Formalin-fixed, paraffin-embedded tissue samples from 30 invasive carcinomas, 7 benign lesions and two normal mammary glands were analyzed. Tumour features with prognostic value were recorded. The expression of protein HER-2 was analyzed by immunohistochemistry and the number of gene copies by means of DNA chromogenic <it>in situ </it>hybridization.</p> <p>Results</p> <p>Immunohistochemical HER-2 protein overexpression was found in 40% of feline mammary carcinomas, a percentage higher to that observed in human breast carcinoma. As in women, feline tumours with HER-2 protein overexpression had pathological features of high malignancy. However, amplification of HER-2 was detected in 16% of carcinomas with protein overexpression, a percentage much lower than that observed in their human counterpart.</p> <p>Conclusion</p> <p>Feline mammary carcinoma would be a suitable natural model of that subset of human breast carcinomas with HER-2 protein overexpression without gene amplification.</p

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

OBJECTIVE—Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue

Willing and able: action-state orientation and the relation between procedural justice and employee cooperation

Existing justice theory explains why fair procedures motivate employees to adopt cooperative goals, but it fails to explain how employees strive towards these goals. We study self-regulatory abilities that underlie goal striving; abilities that should thus affect employees’ display of cooperative behavior in response to procedural justice. Building on action control theory, we argue that employees who display effective self-regulatory strategies (action oriented employees) display relatively strong cooperative behavioral responses to fair procedures. A multisource field study and a laboratory experiment support this prediction. A subsequent experiment addresses the process underlying this effect by explicitly showing that action orientation facilitates attainment of the cooperative goals that people adopt in response to fair procedures, thus facilitating the display of actual cooperative behavior. This goal striving approach better integrates research on the relationship between procedural justice and employee cooperation in the self-regulation and the work motivation literature. It also offers organizations a new perspective on making procedural justice effective in stimulating employee cooperation by suggesting factors that help employees reach their adopted goals

Water oxidation at hematite photoelectrodes: the role of surface states

Hematite (α-Fe2O3) constitutes one of the most promising semiconductor materials for the conversion of sunlight into chemical fuels by water splitting. Its inherent drawbacks related to the long penetration depth of light and poor charge carrier conductivity are being progressively overcome by employing nanostructuring strategies and improved catalysts. However, the physical–chemical mechanisms responsible for the photoelectrochemical performance of this material (J(V) response) are still poorly understood. In the present study we prepared thin film hematite electrodes by atomic layer deposition to study the photoelectrochemical properties of this material under water-splitting conditions. We employed impedance spectroscopy to determine the main steps involved in photocurrent production at different conditions of voltage, light intensity, and electrolyte pH. A general physical model is proposed, which includes the existence of a surface state at the semiconductor/liquid interface where holes accumulate. The strong correlation between the charging of this state with the charge transfer resistance and the photocurrent onset provides new evidence of the accumulation of holes in surface states at the semiconductor/electrolyte interface, which are responsible for water oxidation. The charging of this surface state under illumination is also related to the shift of the measured flat-band potential. These findings demonstrate the utility of impedance spectroscopy in investigations of hematite electrodes to provide key parameters of photoelectrodes with a relatively simple measurement