Effect of Electrically Mediated Intratumor and Intramuscular Delivery of a Plasmid Encoding IFN α on Visible B16 Mouse Melanomas

Interferon α may be used as a single agent therapy for metastatic malignant melanoma or as an adjuvant to chemotherapy. Delivery of interferon α by gene therapy offers an alternative to recombinant protein therapy. Electrically mediated delivery enhances plasmid expression in a number of tissues, for instance skin, liver, muscle and tumors including melanomas. Here we compare the effect of delivery of a plasmid encoding mouse interferon α on growth of visible B16 mouse melanomas following electrically mediated delivery to muscle or directly to the tumor. Intratumoral delivery of interferon α plasmid not only slows melanoma growth, but induces complete, long term, regression. This effect was not observed after intramuscular delivery

Development of fragment-specific osteopontin antibodies and ELISA for quantification in human metastatic breast cancer

Background: Osteopontin (OPN) is associated with human cancers, and circulating blood OPN may have diagnostic or prognostic value in clinical oncology. Methods: To evaluate OPN as a cancer biomarker, we generated and characterized five novel mouse monoclonal antibodies against the human full-length OPN (fl-OPN). Epitopes recognized by four antibodies (2C5, 2F10, 2H9, and 2E11) map to N-terminal OPN (aa1-166); one (1F11) maps to C-terminal OPN (aa167-314). These antibodies recognize recombinant and native OPN by ELISA and immunoblot, cross reacting with human and mouse OPN. Two of these novel antibodies ( 2F10 and 1F11) were used to develop a quantitative enzyme linked immunosorbent assay ( ELISA) for fl-OPN. Results: In comparison with commercially available ELISAs, our assay had high accuracy in measuring fl-OPN standards, and high sensitivity. Specifically, our ELISA has a linear dose response between 0.078 ng/ml- 10 ng/ml, with a sensitivity of 13.9 pg/ml. We utilized this assay to quantify fl-OPN in the plasma of healthy volunteers in comparison with patients with metastatic breast cancer. The average circulating plasma fl-OPN in healthy volunteers was 1.2 ng/ml, compared to 4.76 ng/ml in patients with metastatic breast cancer (p = 0.0042). Although the increase in fl-OPN in cancer patients is consistent with previous studies, the measured quantity varied greatly between all existing fl-OPN ELISAs. Conclusion: Because OPN is a complex molecule with diversity from alternative splicing, post-translational modification, extracellular proteolytic modification, and participation in protein complexes, we suggest that further understanding of specific isoform recognition of multiple OPN species is essential for future studies of OPN biomarker utility

Synthetic biodegradable hydrogel delivery of demineralized bone matrix for bone augmentation in a rat model

There exists a strong clinical need for a more capable and robust method to achieve bone augmentation, and a system with fine-tuned delivery of demineralized bone matrix (DBM) has the potential to meet that need. As such, the objective of the present study was to investigate a synthetic biodegradable hydrogel for the delivery of DBM for bone augmentation in a rat model. Oligo(poly(ethylene glycol) fumarate) (OPF) constructs were designed and fabricated by varying the content of rat-derived DBM particles (either 1:3, 1:1 or 3:1 DBM:OPF weight ratio on a dry basis) and using two DBM particle size ranges (50–150 or 150–250 μm). The physical properties of the constructs and the bioactivity of the DBM were evaluated. Selected formulations (1:1 and 3:1 with 50–150 μm DBM) were evaluated in vivo compared to an empty control to investigate the effect of DBM dose and construct properties on bone augmentation. Overall, 3:1 constructs with higher DBM content achieved the greatest volume of bone augmentation, exceeding 1:1 constructs and empty implants by 3- and 5-fold, respectively. As such, we have established that a synthetic, biodegradable hydrogel can function as a carrier for DBM, and that the volume of bone augmentation achieved by the constructs correlates directly to the DBM dose

The interstellar medium and feedback in the progenitors of the compact passive galaxies at z~2

Quenched galaxies at z>2 are nearly all very compact relative to z~0, suggesting a physical connection between high stellar density and efficient, rapid cessation of star-formation. We present restframe UV spectra of Lyman-break galaxies (LBGs) at z~3 selected to be candidate progenitors of quenched galaxies at z~2 based on their compact restframe optical sizes and high surface density of star-formation. We compare their UV properties to those of more extended LBGs of similar mass and star formation rate (non-candidates). We find that candidate progenitors have faster ISM gas velocities and higher equivalent widths of interstellar absorption lines, implying larger velocity spread among absorbing clouds. Candidates deviate from the relationship between equivalent widths of Lyman-alpha and interstellar absorption lines in that their Lyman-alpha emission remains strong despite high interstellar absorption, possibly indicating that the neutral HI fraction is patchy such that Lyman-alpha photons can escape. We detect stronger CIV P-Cygni features (emission and absorption) and HeII emission in candidates, indicative of larger populations of metal rich Wolf-Rayet stars compared to non-candidates. The faster bulk motions, broader spread of gas velocity, and Lyman-alpha properties of candidates are consistent with their ISM being subject to more energetic feedback than non-candidates. Together with their larger metallicity (implying more evolved star-formation activity) this leads us to propose, if speculatively, that they are likely to quench sooner than non-candidates, supporting the validity of selection criteria used to identify them as progenitors of z~2 passive galaxies. We propose that massive, compact galaxies undergo more rapid growth of stellar mass content, perhaps because the gas accretion mechanisms are different, and quench sooner than normally-sized LBGs at these early epochs.Comment: Accepted for publication in the Astrophysical Journa

Effect of local environment and stellar mass on galaxy quenching and morphology at 0.5<z<2.00.5<z<2.0

We study galactic star-formation activity as a function of environment and stellar mass over 0.5<z<2.0 using the FourStar Galaxy Evolution (ZFOURGE) survey. We estimate the galaxy environment using a Bayesian-motivated measure of the distance to the third nearest neighbor for galaxies to the stellar mass completeness of our survey, $\log(M/M_\odot)>9 (9.5)$ at z=1.3 (2.0). This method, when applied to a mock catalog with the photometric-redshift precision ($\sigma_z / (1+z) \lesssim 0.02$), recovers galaxies in low- and high-density environments accurately. We quantify the environmental quenching efficiency, and show that at z> 0.5 it depends on galaxy stellar mass, demonstrating that the effects of quenching related to (stellar) mass and environment are not separable. In high-density environments, the mass and environmental quenching efficiencies are comparable for massive galaxies ($\log (M/M_\odot)\gtrsim$ 10.5) at all redshifts. For lower mass galaxies ($\log (M/M)_\odot) \lesssim$ 10), the environmental quenching efficiency is very low at $z\gtrsim$ 1.5, but increases rapidly with decreasing redshift. Environmental quenching can account for nearly all quiescent lower mass galaxies ($\log(M/M_\odot) \sim$ 9-10), which appear primarily at $z\lesssim$ 1.0. The morphologies of lower mass quiescent galaxies are inconsistent with those expected of recently quenched star-forming galaxies. Some environmental process must transform the morphologies on similar timescales as the environmental quenching itself. The evolution of the environmental quenching favors models that combine gas starvation (as galaxies become satellites) with gas exhaustion through star-formation and outflows ("overconsumption"), and additional processes such as galaxy interactions, tidal stripping and disk fading to account for the morphological differences between the quiescent and star-forming galaxy populations.Comment: 29 pages, 15 figure, accepted for publication in Ap

Thoracic endovascular aneurysm repair, race, and volume in thoracic aneurysm repair

BackgroundVolume-based disparities in surgical care are often associated with poorer results in African American patients. We examined the effect of treatment patterns and outcomes, by race, for isolated thoracic aortic aneurysm (TAA).MethodsUsing Medicare claims (1999-2007), we studied all patients undergoing repair of TAAs, via open surgery or thoracic endovascular aneurysm repair (TEVAR). We studied 30-day mortality and complications by race, procedure type, and hospital volume.ResultsWe studied 12,573 patients who underwent open TAA repair (4% of whom were black) and 2732 patients who underwent TEVAR (8% of whom were black). In open repair, black patients had higher 30-day mortality than white patients (18% vs 10%; P < .001), while mortality rates were similar with TEVAR (8% black vs 9% white; P = .56). For open repair, black patients were more likely to undergo surgery at low-volume hospitals, where overall operative mortality was highest (14% at very low-volume hospitals, 7% at very high-volume hospitals; P < .001). However, for TEVAR, black patients were not more likely to undergo repair at low-volume hospitals, and mortality differences were not evident across volume strata (9% at very low-volume hospitals, 7% at very high-volume hospitals; P = .328). Multivariable analyses adjusting for age, sex, race, comorbidity, and volume confirmed that increased perioperative mortality was associated with black race for open surgery (OR, 2.0, 95% CI, 1.5-2.5; P < .001) but not TEVAR (OR, 0.9, 95% CI, 0.6-1.5; P = .721).ConclusionsWhile racial disparities in surgical care have a significant effect on mortality with open thoracoabdominal aortic aneurysm repair, black patients undergoing TEVAR obtain similar outcomes as white patients. New technology can limit the effect of racial disparities in surgical care

The Spitzer c2d Survey of Large, Nearby, Interstellar Clouds. VIII. Serpens Observed with MIPS

We present maps of 1.5 deg^2 of the Serpens dark cloud at 24, 70, and 160 μm observed with the Spitzer Space Telescope MIPS camera. We describe the observations and briefly discuss the data processing carried out by the c2d team on these data. More than 2400 compact sources have been extracted at 24 μm, nearly 100 at 70 μm, and four at 160 μm. We estimate completeness limits for our 24 μm survey from Monte Carlo tests with artificial sources inserted into the Spitzer maps. We compare source counts, colors, and magnitudes in the Serpens cloud to two reference data sets: a 0.50 deg^2 set on a low-extinction region near the dark cloud, and a 5.3 deg^2 subset of the SWIRE ELAIS N1 data that was processed through our pipeline. These results show that there is an easily identifiable population of young stellar object candidates in the Serpens cloud that is not present in either of the reference data sets. We also show a comparison of visual extinction and cool dust emission illustrating a close correlation between the two and find that the most embedded YSO candidates are located in the areas of highest visual extinction

Epistemic Beliefs: Relationship to Future Expectancies and Quality of Life in Cancer Patients.

CONTEXT: Expectations about the future (future expectancies) are important determinants of psychological well-being among cancer patients, but the strategies patients use to maintain positive and cope with negative expectancies are incompletely understood. OBJECTIVES: To obtain preliminary evidence on the potential role of one strategy for managing future expectancies: the adoption of epistemic beliefs in fundamental limits to medical knowledge. METHODS: A sample of 1307 primarily advanced-stage cancer patients participating in a genomic tumor testing study in community oncology practices completed measures of epistemic beliefs, positive future expectancies, and mental and physical health-related quality of life (HRQOL). Descriptive and linear regression analyses were conducted to assess the relationships between these factors and test two hypotheses: 1) epistemic beliefs affirming fundamental limits to medical knowledge ( fallibilistic epistemic beliefs ) are associated with positive future expectancies and mental HRQOL, and 2) positive future expectancies mediate this association. RESULTS: Participants reported relatively high beliefs in limits to medical knowledge (M = 2.94, s.d.=.67) and positive future expectancies (M = 3.01, s.d.=.62) (range 0-4), and relatively low mental and physical HRQOL. Consistent with hypotheses, fallibilistic epistemic beliefs were associated with positive future expectancies (b = 0.11, SE=.03, P\u3c 0.001) and greater mental HRQOL (b = 0.99, SE=.34, P = 0.004); positive expectancies also mediated the association between epistemic beliefs and mental HRQOL (Sobel Z=4.27, P\u3c0.001). CONCLUSIONS: Epistemic beliefs in limits to medical knowledge are associated with positive future expectancies and greater mental HRQOL; positive expectancies mediate the association between epistemic beliefs and HRQOL. More research is needed to confirm these relationships and elucidate their causal mechanisms

Evolution of mud-crack patterns during repeated drying cycles

In mud, crack patterns are frequently seen with either an approximately rectilinear or hexagonal tiling. Here we show, experimentally, how a desiccation crack pattern changes from being dominated by 90° joint angles, to 120° joint angles. Layers of bentonite clay, a few mm thick, were repeatedly wetted and dried. When dried, the layers crack. These cracks visibly close when rewetted, but a similar crack pattern forms when the layer is redried, with cracks forming along the lines of previously open cracks. Time-lapse photography was used to show how the sequence in which individual cracks open is different in each generation of drying. The geometry of the crack pattern was observed after each of 25 generations of wetting and drying. The angles between cracks were found to approach 120°, with a relaxation time of approximately 4 generations. This was accompanied by a gradual change in the position of the crack vertices, as the crack pattern evolved. A simple model of crack behavior in a layer where the positions of previously open cracks define lines of weakness is developed to explain these observations