Prostate cancer PET bioprobes: synthesis of [18F]-radiolabeled hydroxyflutamide derivatives

Approximately 80-90% of prostate cancers are androgen dependent at initial diagnosis. The androgen receptor (AR) is present in most advanced prostate cancer specimens and is believed to have a critical role in its development. Today, treatment of prostate cancer is done by inhibition of AR using antiandrogens such as flutamide (pro-drug of hydroxyflutamide), nilutamide, and bicalutamide. However, there is currently no noninvasive imaging modalities to detect, guide, and monitor specific treatment of AR-positive prostate cancer. (R)-3-Bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-propanamide [18F]-1 and N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide [18F]-2, derivatives of hydroxyflutamide, were synthesized as a fluorine-containing imaging agent candidates. A three-step fluorine-18 radiosynthesis route was developed, and the compounds were successfully labeled with a 10+/-3% decay corrected radiochemical yield, 95% radiochemical purity, and a specific activity of 1500+/-200 Ci/mmol end of bombardment (n = 10). These labeled biprobes not only may enable for the future quantitative molecular imaging of AR-positive prostate cancer using positron emission tomography but may also allow for image-guided treatment of prostate cancer.     

Active Nematocyst Isolation Via Nudibranchs

Cnidarian venoms are potentially valuable tools for biomedical research and drug development. They are contained within nematocysts, the stinging organelles of cnidarians. Several methods exist for the isolation of nematocysts from cnidarian tissues; most are tedious and target nematocysts from specific tissues. We have discovered that the isolated active nematocyst complement (cnidome) of several sea anemone (Cnidaria: Anthozoa) species is readily accessible. These nematocysts are isolated, concentrated, and released to the aqueous environment as a by-product of aeolid nudibranch Spurilla neapolitana cultures. S. neapolitana feed on venomous sea anemones laden with stinging nematocysts. The ingested stinging organelles of several sea anemone species are effectively excreted in the nudibranch feces. We succeeded in purifying the active organelles and inducing their discharge. Thus, our current study presents the attractive possibility of using nudibranchs to produce nematocysts for the investigation of novel marine compounds.     

L’industrie microlithique du Paléolithique inférieur de Bizat Ruhama, Israël

Bizat Ruhama is a lower Palaeolithic site in the southern coastal plain of Israel. The site was recently dated to ca. 1ma. In terms of lithic industry, Bizat Ruhama is a unique phenomenon amongst the Lower Palaeolithic sites in the Levant. The lithic assemblage of the site is characterized by the production of small (ca. 25mm) tools, flakes and cores. An in-depth technotypological study was made in attempt to reconstruct the production mode of these artifacts. The results presented here reveal a well-developed cognitive production process, which includes selection of special-sized raw material, production of desired blanks and their subsequent shaping into tools. The implications of this study contribute significantly to our understanding of the phenomenon of lower Palaeolithic microlithic industries in Eurasia.     

Exploring the charge space of protein-protein association: a proteomic study

The rate of association of a protein complex is a function of an intrinsic basal rate and of the magnitude of electrostatic steering. In the present study we analyze the contribution of electrostatics towards the association rate of proteins in a database of 68 transient hetero-protein-protein complexes. Our calculations are based on an upgraded version of the computer algorithm PARE, which was shown to successfully predict the impact of mutations on k(on) by calculating the difference in Columbic energy of interaction of a pair of proteins. HyPare (http://bip.weizmann.ac.il/HyPare), automatically calculates the impact of mutations on a per-residue basis for all residues of a protein-protein interaction, achieving a precision similar to that of PARE. Our calculations show that electrostatics play a marginal role (<10 fold) in determining the rate of association for about half of the complexes in the database. Strong electrostatic steering, which results in an increase of over 100-fold in k(on), was calculated for about 25% of the complexes. Applying HyPare to all 68 complexes in the database shows that a small number of residues are hotspots for association. About 40% of the hotspots are calculated to increase the rate of association upon mutation, and thus increase binding affinity. This is a much higher ratio than found for hotspots for dissociation, where the large majority cause weaker binding. About 40% of the hotspots are located outside the physical boundary of the binding site, making them ideal candidates for protein engineering. Our data shows that a majority of protein-protein complexes are not optimized for fast association. Hotspots are not evenly distributed between all types of amino acids. About 75% of all hotspots are of charged residues. This is understandable, as a charge-reverse mutant changes the total charge by 2. The small number of hydrophobic residues that are hotspots upon mutation probably relates to their location and surrounding. For 18 out of the 68 complexes in the database, experimental values of k(on) are available. For these, a basal rate of association was calculated to be in the range of 10(4)M(-1)s(-1) to 10(7)M(-1)s(-1). Some of these rates were verified independently from experimental mutant data. The basal rates were correlated with the size of the proteins and the shape of the interface.     

p53 in Bronchial Club Cells Facilitates Chronic Lung Inflammation by Promoting Senescence

1. Download high-res image (193KB)
2. Download full-size image

     

In vitro elicitation of cytotoxic response against a nonimmunogenic murine tumor by allosensitization

Summary The murine lymphoma (thymoma) PIR-2 of C57BL/6 origin, primarily induced in our laboratory by fractionated X-ray irradiation, has been shown to be nonimmunogenic by its failure to immunize syngeneic mice in vivo or to evoke a cytotoxic response in primary mixed lymphocyte-tumor cell cultures (MLTC) in vitro. We were able, however, to demonstrate the existence of anti-PIR-2 cytotoxic cells among allogeneic-primed C57BL/6 responding lymphocytes using the technique of limiting dilution cultures (LDC). The frequency of anti-PIR-2 cytotoxic cells among C57BL/6 lymphocytes sensitized against BALB/c splenocytes in mixed leukocyte culture (MLC) was 1/20 to 1/40, and the cytotoxic activity of positive LDC wells against PIR-2 reached 60% as determined by a 4-h ⁵¹Cr-release assay. The frequency of anti-PIR-2 cytotoxic cells could be increased two- to 10-fold (up to 1/4) by removing nylon-wool-adherent cells from the primed cell population and/or by enriching the primed lymphoblast population on a Percoll density gradient. Anti-PIR-2 cytotoxic cells were found to be Thy1⁺; Lytl^–2⁺ cells. Clones isolated from the LDC wells manifested strong cytotoxic activity toward PIR-2 cells and the stimulating BALB/c splenocytes but not against other H-2^b tumor lines or C57BL/6 splenocytes. We suggest that the procedure of allostimulation in MLC-LDC is an effective in vitro means of generating highly reactive cytotoxic cells against poorly immunogenic neoplasms.     

Satelliten-Telemetrie der Jahreswanderungen eines Wei?storchsCiconia ciconia und Diskussion der Orientierungsmechanismen des Heimzugs

In a female White Stork the complete migration cycle could be tracked by satellite from the nesting site to the wintering grounds in the Sudan and Tanzania and back to the nest. The migration route extended over 16 000 km, autumn migration lasted 100 days, homeward migration 70 days, wintering 58 and 41 days in northeastern and southeastern Africa, respectively. The maximum daily route was about 350 km. Up to Turkey the bird migrated together with its male. Homeward migration was performed within a relatively narrow corridor in which autumn migration took place, but in detail the routes of the two migratory seasons showed substantial differences. These data together with those from some raptors in which complete annual migration cycles could be tracked indicate that homeward migration is based on navigation (vector navigation and/or true navigation) rather than on route reversal.     

Satelliten-Telemetrie beim Wei?storchCiconia ciconia: Wanderung eines Ost-Storchs westlich bis Nigeria

A male White Stork, for the first time equipped with a mini-transmitter operated by a solar battery, was tracked on the eastern migration route from E Germany to central African winter quarters and during part of the return migration, for a total distance of about 10 000 km. The individual moved westward into Nigeria, i.e. into the wintering area of western Storks. Since a number of other eastern Storks were tracked as far as Chad, the possibility is discussed that individuals migrating to central Africa along the eastern or western route may eventually return on the opposite route when attracted to flocks of the population from the other side of the migration divide. Some ringing recoveries are consistent with a U-shaped abmigration.     

Recruitment,mortality, and resilience potential of scleractinian corals at Eilat,Red Sea

Events of mass coral bleaching and mortality have increased in recent decades worldwide, making coral recruitment more important than ever in sustaining coral-reef ecosystems and ensuring their resilience. During the last four decades, the coral reefs of Eilat have undergone severe deterioration due to both anthropogenic and natural causes. Recruitment failure has been frequently suggested as one of the main mechanisms underlying this deterioration. Here we assess the demographic replenishment and resilience potential of the local reefs, i.e., the potential for new sexually derived corals to recruit and exceed the community’s mortality rate. We present a detailed analysis of coral community demography, obtained by means of high-resolution photographic monitoring of permanently marked plots. Coral spats as small as 1 mm were documented and the detailed dynamics of coral recruitment and mortality were recorded, in addition to other common ecological measurements. The cumulative quantity of recruited individuals was twofold to fivefold higher than total mortality. The most significant predictor variable for coral recruitment among all ecological parameters measured was the available substrate for settlement, and the survival of recruited corals was correlated with reef structural complexity. Two consecutive annual reproductive seasons (June–September of each year) with high recruitment rates were monitored. Combined with the high survival of recruits and the increase in coral live cover and abundance, the findings from this study indicate an encouraging potential for recovery of these reefs.