Relation between composition and vacant oxygen sites in the mixed ionicelectronic conductors La5.4W1 yMyO12 delta M Mo, Re; 0 lt; y lt; 0.2 and their mother compound La6 xWO12 delta 0.4 lt; x lt; 0.8

A detailed analysis of specimen composition, water uptake and their interrelationship in the systems La6 xWO12 amp; 948; 0.4 amp; 8804; x amp; 8804;0.8 and La6 xW1 yMyO12 amp; 948; 0 amp; 8804;y amp; 8804;0.2; M Mo, Re is presented. The three specimen series were investigated in dry and wet D2O conditions. A systematic trend in mass loss and onset temperature variation was observed in La6 xWO12 amp; 948; 0.4 amp; 8804;x amp; 8804;0.8 . Even very small amounts lt; 1 wt of secondary phases were found to notably modify the specimen s water uptake and onset temperature of mass loss. The theoretical model for vacancy concentration available was used to calculate the vacant oxygen sites starting from mass loss values determined by thermogravimetry. A discrepancy between the calculated and observed concentration of vacant oxygen sites is observed for all three systems. The effect of substitution of W by Re or Mo on the vacancy amount is explained taking into account diffraction measurements and information on the oxidation state of the substituting elements Mo and R

A time-resolved fluorescence immunoassay for the measurement of testosterone in saliva: Monitoring of testosterone replacement therapy with testosterone buciclate

Monitoring of testosterone replacement therapy requires a reliable method for testosterone measurement. Determination of salivary testosterone, which reflects the hormone's biologically active plasma fraction, is a superior technique for this purpose. The aim of the present study was to establish a new sensitive time-resolved fluorescence immunoassay for the accurate measurement of testosterone levels in saliva and to validate it by monitoring testosterone replacement therapy in eight hypogonadal men. A clinical phase I- study with the new ester testosterone buciclate was performed to search for new testosterone preparations to produce constant serum levels in the therapy of male hypogonadism. After two control examinations eight male patients with primary hypogonadism were randomly assigned to two treatment groups (n = 2x4) and given single doses of either 200 mg (group I) or 600 mg (group II) testosterone buciclate intramuscularly. Saliva and blood samples were obtained 1, 2, 3, 5 and 7 days post injection and then weekly for three months. The time-resolved fluorescence immunoassay for salivary testosterone shows a detection limit of 16 pmol/l, an intra-assay CV of 8.9% (at a testosterone concentration of 302 pmol/l), an inter-assay CV of 8.7% (at a testosterone concentration of 305 pmol/l) and a good correlation with an established radioimmunsassay of r = 0.89. The sample volume required by this method is only 180 mu l for extraction and duplicate determination. The assay procedure requires no more than three hours. In group I (200 mg) testosterone did not increase to normal levels either in saliva or in serum. However, in group II, androgen levels increased significantly and were maintained in the normal range for up to 12 weeks with maximal salivary testosterone levels of 303 +/- 18 pmol/l (mean+/-SE) and maximal testosterone levels of 13.1 +/- 0.9 nmol/l (mean+/-SE) in serum in study week 6 and 7. The time-resolved fluorescence immunoassay for salivary testosterone provides a useful tool for monitoring androgen status in men and women and is well suited for the follow-up of testosterone replacement therapy on an outpatient basis. The long-acting ester testosterone buciclate is a promising agent for substitution therapy of male hypogonadism and in combination with testosterone monitoring in saliva offers an interesting new perspective for male contraception

GMP manufacturing of Vvax001, a therapeutic anti-HPV vaccine based on recombinant viral particles

Therapeutic vaccination is being explored as a treatment strategy for the treatment of patients with primary or metastatic tumours. We developed a vaccine targeted to Human papillomavirus (HPV)-induced tumours based on recombinant Semliki Forest virus (rSFV) encoding a fusion protein of the E6 and E7 proteins of HPV type 16. To enable a phase I clinical trial with this vaccine, Vvax001, a Good Manufacturing Practice (GMP)-compliant manufacturing process was set up and clinical material was produced. Upstream production of the clinical material resulted in viral titers from 2.4 × 107 to 1.3 × 109 infectious particles/ mL in the harvest. The total volume of 6.0 liter crude virus was purified in 13 consecutive downstream purification runs. The mean titer after purification was 4.0 × 108 infectious particles/ mL and the mean recovery was 19%. Finally, clinical material was filled at a target concentration of 1.25 × 108 infectious particles/mL. Release testing included tests for viral titer and virus identity, biological activity, sterility, bacterial endotoxins, adventitious viruses and absence of replication competent virus. The product complied with all specifications and was released for use as an investigational medicinal product. This is the first GMP production process developed for a SFV-based therapeutic vaccine. The vaccine, Vvax001 is targeted to HPV and has shown promising results in preclinical studies. The GMP-produced Vvax001 material met the quality criteria and was of sufficient quantity to enable assessment of its immunogenicity, safety and efficacy in a clinical setting

Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models

Improving the antitumor potency of current oncolytic adenoviruses represents one of the major challenges in development of these viruses for clinical use. We have generated an oncolytic adenovirus carrying the safety-enhancing E1A Delta 24 deletion, the potency-enhancing T1 mutation, and the infectivity-enhancing fiber RGD modification. The results of in vitro cytotoxicity assays on 15 human cancer cell lines derived from different tumor types demonstrated that ORCA-010 is more potent than Ad5-Delta 24RGD or ONYX-015. As ORCA-010 will initially be developed for the treatment of prostate cancer, selectivity experiments were performed using primary human prostate cells. ORCA-010 killed cancer cells more effectively than these primary human cells. In both primary prostate fibroblasts and epithelial cells, ORCA-010 was as safe as Ad5-Delta 24RGD. Evaluation of ORCA-010 in in vivo xenograft tumor models in nude mice showed that ORCA-010 significantly inhibited growth of prostate, lung, and ovarian tumors and conferred prolonged survival of tumor-bearing animals. Furthermore, we observed a substantial increase in infectious viral particles in tumors injected with ORCA-010. The number of infectious viral particles increased after treatment and infectious particles remained present up to at least 4 weeks posttreatment. Intratumoral virus replication was associated with substantial necrosis and fibrosis. In conclusion, ORCA-010 is more potent than earlier generation oncolytic adenoviruses, without demonstrating increased toxicity. ORCA-010 exerted strong in vivo antitumor activity and is therefore a suitable candidate for clinical evaluation

Experimental Observation of Quantum Confinement in the Conduction Band of CdSe Quantum Dots

Recent theoretical descriptions as to the magnitude of effect that quantum confinement has on he conduction band (CB) of CdSe quantum dots (QD) have been conflicting. In this manuscript, we experimentally identify quantum confinement effects in the CB of CdSe QDs for the first time. Using X-ray absorption spectroscopy, we have unambiguously witnessed the CB minimum shift to higher energy with decreasing particle size and have been able to compare these results to recent theories. Our experiments have been able to identify which theories correctly describe the CB states in CdSe QDs. In particular, our experiments suggest that multiple theories describe the shifts in the CB of CdSe QDs and are not mutually exclusive

Frequency-Dependent Properties of a Fluid Jet Stimulus: Calibration, Modeling, and Application to Cochlear Hair Cell Bundles

The investigation of small physiological mechano-sensory systems, such as hair cells or their accessory structures in the inner ear or lateral line organ, requires mechanical stimulus equipment that allows spatial manipulation with micrometer precision and stimulation with amplitudes down to the nanometer scale. Here, we describe the calibration of a microfluid jet produced by a device that was designed to excite individual cochlear hair cell bundles or cupulae of the fish superficial lateral line system. The calibration involves a precise definition of the linearity and time- and frequency-dependent characteristics of the fluid jet as produced by a pressurized fluid-filled container combined with a glass pipette having a microscopically sized tip acting as an orifice. A procedure is described that can be applied during experiments to obtain a fluid jet’s frequency response, which may vary with each individual glass pipette. At small orifice diameters (<15 μm), the fluid velocity of the jet is proportional to the displacement of the piezoelectric actuator pressurizing the container’s volume and is suitable to stimulate the hair bundles of sensory hair cells. With increasing diameter, the fluid jet velocity becomes proportional to the actuator’s velocity. The experimentally observed characteristics can be described adequately by a dynamical model of damped fluid masses coupled by elastic components

The M/GP5 Glycoprotein Complex of Porcine Reproductive and Respiratory Syndrome Virus Binds the Sialoadhesin Receptor in a Sialic Acid-Dependent Manner

The porcine reproductive and respiratory syndrome virus (PRRSV) is a major threat to swine health worldwide and is considered the most significant viral disease in the swine industry today. In past years, studies on the entry of the virus into its host cell have led to the identification of a number of essential virus receptors and entry mediators. However, viral counterparts for these molecules have remained elusive and this has made rational development of new generation vaccines impossible. The main objective of this study was to identify the viral counterparts for sialoadhesin, a crucial PRRSV receptor on macrophages. For this purpose, a soluble form of sialoadhesin was constructed and validated. The soluble sialoadhesin could bind PRRSV in a sialic acid-dependent manner and could neutralize PRRSV infection of macrophages, thereby confirming the role of sialoadhesin as an essential PRRSV receptor on macrophages. Although sialic acids are present on the GP3, GP4 and GP5 envelope glycoproteins, only the M/GP5 glycoprotein complex of PRRSV was identified as a ligand for sialoadhesin. The interaction was found to be dependent on the sialic acid binding capacity of sialoadhesin and on the presence of sialic acids on GP5. These findings not only contribute to a better understanding of PRRSV biology, but the knowledge and tools generated in this study also hold the key to the development of a new generation of PRRSV vaccines