Co-administration of a DNA vaccine encoding the prostate specific membrane antigen and CpG oligodeoxynucleotides suppresses tumor growth

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well characterized prostate-specific tumor associated antigen. Its expression is elevated in prostate carcinoma, particularly in metastatic and recurrent lesions. These observations suggest that PSMA can be used as immune target to induce tumor cell-specific recognition by the host and, consequently tumor rejection. We utilized a DNA-based vaccine to specifically enhance PSMA expression. An immune modulator, such as CpG oligodeoxynucleotides which promote Th1-type immune responses was combined to increase the efficacy of tumor recognition and elimination. METHODS: A eukaryotic expression plasmid pCDNA3.1-PSMA encoding full-length PSMA was constructed. C57BL/6 mice were immunized with endotoxin-free pCDNA3.1-PSMA alone or in combination with CpG oligodeoxynucleotides by intramuscular injection. After 4 immunizations, PSMA specific antibodies and cytotoxic T lymphocyte reactivity were measured. Immunized C57BL/6 mice were also challenged subcutaneously with B16 cells transfected with PSMA to evaluate suppression of tumor growth. RESULTS: Vaccine-specific cytotoxic T lymphocytes reactive with B16 cells expressing PSMA could be induced with this treatment schedule. Immune protection was observed in vaccinated mice as indicated by increased tumor growth in the control group (100%) compared with the groups vaccinated with DNA alone (66.7%) or DNA plus CpG oligodeoxynucleotides (50%) respectively. Average tumor volume was smaller in vaccinated groups and tumor-free survival time was prolonged by the vaccination. CONCLUSION: The current findings suggest that specific anti-tumor immune response can be induced by DNA vaccines expressing PSMA. In addition, the suppression of in vivo growth of tumor cells expressing PSMA was augmented by CpG oligodeoxynucleotides. This strategy may provide a new venue for the treatment of carcinoma of prostate after failure of standard therapy

Apical conicity ratio: A new index on left ventricular apical geometry after myocardial infarction

ObjectiveOur objective was to introduce a new index to evaluate left ventricular aneurysm by quantitative analysis of left ventricular apical geometry.MethodsA total of 116 selected subjects underwent magnetic resonance imaging, 28 healthy volunteers, 29 patients with dilated cardiomyopathy, and 59 patients with ischemic heart disease (26 with left ventricular aneurysm; 33 with no aneurysm). The apical conicity ratio was calculated as the ratio of left ventricular apical area over apical triangle.ResultsDiastolic apical conicity ratio of patients with left ventricular aneurysm was 1.62 ± 0.20 and systolic apical conicity ratio was 1.78 ± 0.43. After left ventricular reconstruction, the diastolic apical conicity ratio decreased to 1.47 ± 0.23 and the systolic ratio to 1.51 ± 0.21, which came close to the normal level, whereas other global indices remained. In patients with dilated cardiomyopathy, sphericity index and eccentricity index increased significantly without changes in the apical conicity ratio. Among patients with ischemic heart disease, the apical conicity ratio of the group with left ventricular aneurysm was significantly higher than that of the group without an aneurysm when the other indices between the 2 groups showed no statistically difference. Receiver operating characteristic curves showed only apical conicity ratio had high power of discriminating left ventricular aneurysm from no aneurysm.ConclusionsThe new index, apical conicity ratio, can be used to quantify the regional left ventricular deformation, especially in patients with left ventricular aneurysm resulting from myocardial infarction

Promjena tlačne čvrstoće zida nakon korozije sulfatom uz visoku koncentraciju Ca2+

At the bedrock section of the auxiliary shaft of the Tong-ting coal mine, the sidewall has varying degradation degrees in different parts. The part on which water flowed is barely corroded, whereas the moist part near the pouring joints is seriously corroded. We first studied the mechanism of this phenomenon by chromatography, X-ray diffraction, and energy-dispersive X-ray spectroscopy. We then used simplified models built by particle flow code software (i.e., particle flow code in three dimensions, PFC3D) to analyse how increasing degradation depth affects compressive strength and failure patterns. The results were as follows. (1) Gypsum and calcite in corrosive water were supersaturated. The part on which water flowed was protected by the crystallized precipitation on the concrete. By contrast, the degradation of the part where water flowed through pouring joints was aggravated by internal crystallization and dissolution. (2) PFC3D numerical simulation indicated that decreases in vertical ultimate stress were strongly linearly correlated with degradation depth. As for the −355.5 m damaged part, reinforcement should be conducted before degradation depth reaches 250 mm. (3) No obvious signs were observed prior to the failure of the corroded sidewall. Therefore, the development of degradation depth should be monitored before degradation parts are reinforced.U pomoćnom oknu rudnika ugljena Tong-ting u pojasu temeljne stijene pojedini dijelovi zida pokazuju različite stupnjeve propadanja. Područja na kojima je tekla voda malo su korodirana, dok su vlažni dijelovi uz izljeve izrazito korodirani. Mehanizmi te pojave najprije su proučavani kromatografijom, rendgenskom difrakcijom i energijski disperzivnom rendgenskom spektroskopijom. Veza između dubine korozije i tlačne čvrstoće te obrasca sloma analizirana je pojednostavljenim modelom utemeljenim na kôdu toka čestica (kôd toka čestica u tri dimenzije, PFC3D). (1) Voda je prezasićena s obzirom na gips i kalcit. Dijelovi preko kojih je voda tekla zaštićeni su precipitatom na betonu. Nasuprot tome, propadanje je pojačano kristalizacijom i otapanjem u nutrini izljeva. (2) Numerička simulacija modelom PFC3D pokazuje linearnu vezu između smanjenja vertikalnog maksimalnog naprezanja i dubine degradacije. Oštećeni dio na −355,5 m trebat će pojačati prije nego korozija dopre do 250 mm dubine. (3) Nisu bili uočeni jasni pokazatelji propadanja prije sloma korodiranog zida. Stoga treba pratiti napredovanje propadanja prije nego uništeni dijelovi budu ojačani

Molecular Optical Imaging with Radioactive Probes

Background: Optical imaging (OI) techniques such as bioluminescence and fluorescence imaging have been widely used to track diseases in a non-invasive manner within living subjects. These techniques generally require bioluminescent and fluorescent probes. Here we demonstrate the feasibility of using radioactive probes for in vivo molecular OI. Methodology/Principal Findings: By taking the advantages of low energy window of light (1.2–3.1 eV, 400–1000 nm) resulting from radiation, radionuclides that emit charged particles such as b + and b 2 can be successfully imaged with an OI instrument. In vivo optical images can be obtained for several radioactive probes including 2-deoxy-2- [ 18 F]fluoro-D-glucos

111In-Labeled Cystine-Knot Peptides Based on the Agouti-Related Protein for Targeting Tumor Angiogenesis

Agouti-related protein (AgRP) is a 4-kDa cystine-knot peptide of human origin with four disulfide bonds and four solvent-exposed loops. The cell adhesion receptor integrin αvβ3 is an important tumor angiogenesis factor that determines the invasiveness and metastatic ability of many malignant tumors. AgRP mutants have been engineered to bind to integrin αvβ3 with high affinity and specificity using directed evolution. Here, AgRP mutants 7C and 6E were radiolabeled with 111In and evaluated for in vivo targeting of tumor integrin αvβ3 receptors. AgRP peptides were conjugated to the metal chelator 1, 4, 7, 10-tetra-azacyclododecane- N, N′, N″, N‴-tetraacetic acid (DOTA) and radiolabeled with 111In. The stability of the radiopeptides 111In-DOTA-AgRP-7C and 111In-DOTA-AgRP-6E was tested in phosphate-buffered saline (PBS) and mouse serum, respectively. Cell uptake assays of the radiolabeled peptides were performed in U87MG cell lines. Biodistribution studies were performed to evaluate the in vivo performance of the two resulting probes using mice bearing integrin-expressing U87MG xenograft tumors. Both AgRP peptides were easily labeled with 111In in high yield and radiochemical purity (>99%). The two probes exhibited high stability in phosphate-buffered saline and mouse serum. Compared with 111In-DOTA-AgRP-6E, 111In-DOTA-AgRP-7C showed increased U87MG tumor uptake and longer tumor retention (5.74 ± 1.60 and 1.29 ± 0.02%ID/g at 0.5 and 24 h, resp.), which was consistent with measurements of cell uptake. Moreover, the tumor uptake of 111In-DOTA-AgRP-7C was specifically inhibited by coinjection with an excess of the integrin-binding peptidomimetic c(RGDyK). Thus, 111In-DOTA-AgRP-7C is a promising probe for targeting integrin αvβ3 positive tumors in living subjects

Metal-Enriched Outflows in the Ultra-Luminous infrared Quasar Q1321+058

Quasar outflows may play important role in the evolution of its host galaxy and central black hole. In this paper, we present a detailed study of multiple outflows in the obscured ultra-luminous infrared quasar Q1321+058. The outflows reveal themselves in the complex optical and UV emission line spectrum, with a broad component blueshifted by 1650 km/s and a narrow component by 360 km/s, respectively.The higher velocity component shows ever strong N III] and strong Si III], in addition to strong [O III]5007 and [Ne III]3869 emission lines, suggesting an overabundance of N and Si relative to C. The abundance pattern is consistent a fast chemical enriching process associated with a recent starburst. The outflow extends to several tens to hundred parsecs from the quasar, and covers only a very small sky. We find that the outflow with line emitting gas is energetically insufficient to remove the ISM of the host galaxy. The velocity range and the column density suggest that the outflow might be part of the low ionization broad absorption line region as seen in a small class of quasars. The optical and UV continuum is starlight-dominated and can be modelled with a young-aged (1 Myr) plus an intermediate-aged (~0.5-1 Gyr) stellar populations, suggesting a fast building of the stellar mass in the host galaxy, consistent with the starburst-type metal abundances inferred from the high velocity outflow spectrum. The broad band spectral energy distribution shows that it is an obscured quasar with its bulk emission in the middle infrared. The star formation rate, independently estimated from UV, far-infrared, and emission line luminosity, is much lower than that is required for the co-evolution of the black hole and its host spheroid.Comment: 31 pages, accepted to Ap

Lyα\alpha Leaks and Reionization

Ly$\alpha$ absorption spectra of QSOs at redshifts $z\simeq6$ show complete Gunn-Peterson absorption troughs (dark gaps) separated by tiny leaks. The dark gaps are from the intergalactic medium (IGM) where the density of neutral hydrogen are high enough to produce almost saturated absorptions, however, where the transmitted leaks come from is still unclear so far. We demonstrate that leaking can originate from the lowest density voids in the IGM as well as the ionized patches around ionizing sources using semi-analytical simulations. If leaks were produced in lowest density voids, the IGM might already be highly ionized, and the ionizing background should be almost uniform; in contrast, if leaks come from ionized patches, the neutral fraction of IGM would be still high, and the ionizing background is significantly inhomogeneous. Therefore, the origin of leaking is crucial to determining the epoch of inhomogeneous-to-uniform transition of the the ionizing photon background. We show that the origin could be studied with the statistical features of leaks. Actually, Ly$\alpha$ leaks can be well defined and described by the equivalent width $W$ and the full width of half area $W_{\rm H}$, both of which are less contaminated by instrumental resolution and noise. It is found that the distribution of $W$ and $W_{\rm H}$ of Ly$\alpha$ leaks are sensitive to the modeling of the ionizing background. We consider four representative reionization models. It is concluded that the leak statistics provides an effective tool to probe the evolutionary history of reionization at $z\simeq5-6.5$. Similar statistics would also be applicable to the reionization of He II at $z \simeq 3$(Abridged)Comment: 11 pages including 10 figures, accepted for publication in MNRA

Non-Invasive Imaging of Cysteine Cathepsin Activity in Solid Tumors Using a 64Cu-Labeled Activity-Based Probe

The papain family of cysteine cathepsins are actively involved in multiple stages of tumorigenesis. Because elevated cathepsin activity can be found in many types of human cancers, they are promising biomarkers that can be used to target radiological contrast agents for tumor detection. However, currently there are no radiological imaging agents available for these important molecular targets. We report here the development of positron emission tomography (PET) radionuclide-labeled probes that target the cysteine cathepsins by formation of an enzyme activity-dependent bond with the active site cysteine. These probes contain an acyloxymethyl ketone (AOMK) functional group that irreversibly labels the active site cysteine of papain family proteases attached to a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tag for labeling with 64Cu for PET imaging studies. We performed biodistribution and microPET imaging studies in nude mice bearing subcutaneous tumors expressing various levels of cysteine cathepsin activity and found that the extent of probe uptake by tumors correlated with overall protease activity as measured by biochemical methods. Furthermore, probe signals could be reduced by pre-treatment with a general cathepsin inhibitor. We also found that inclusion of a Cy5 tag on the probe increased tumor uptake relative to probes lacking this fluorogenic dye. Overall, these results demonstrate that small molecule activity-based probes carrying radio-tracers can be used to image protease activity in living subjects