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Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to innate and adaptive immune response defects in cancers that allow virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized yeast cytosine deaminase gene that converts the prodrug Toca FC (investigational, extended-release 5-FC) into 5-FU within the tumor microenvironment. 5-FU kills infected dividing cancer cells and surrounding tumor, myeloid derived suppressor cells, and tumor associated macrophages, resulting in long-term tumor immunity in preclinical models. Data from a Phase 1 resection trial showed six durable CRs and extended mOS compared to historical controls. The FDA granted Breakthrough Therapy Designation for Toca 511 & Toca FC in the treatment of patients with rHGG. Toca 5 is an international, randomized, open-label Phase 3 trial (NCT02414165) of Toca 511 & Toca FC versus SOC in patients undergoing resection for first or second recurrence of rHGG. Patients will be stratified by IDH1 status, KPS, and geographic region. Primary endpoint is OS, and secondary endpoints are durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. Key inclusion criteria are histologically proven GBM or AA, tumor size ≥1cm and ≤5cm, and KPS ≥70. Immune monitoring and molecular profiling will be performed. Approximately 380 patients will be randomized. An IDMC is commissioned to review the safety and efficacy data which includes 2 interim analyses. Enrollment is ongoing.
Working canines are deployed by the Federal Emergency Management Agency (FEMA), as part of a National Disaster Response Plan. Stress associated with helicopter flight and the resulting physical effects on the dog are unknown. Our objective was to test the hypotheses that (1) helicopter travel affects the physiology and faecal microbiota of working canines, but that (2) physiological consequences of helicopter travel will not negatively affect their work performance. A total of nine FEMA canines were loaded onto helicopters and flown for 30 min in July 2015. Rectal temperature, behavioural stress indicators and saliva swabs (for cortisol) were collected at baseline, loading, mid-flight and post-flight. After flight, canines completed a standardised search exercise to monitor work performance. Faecal samples were collected for microbial DNA extraction and Illumina sequencing. All canines were on a standardised diet (CANIDAE® Grain Free PURE Land®) for 3 weeks prior to the study. Visible indicators of stress were observed at loading and at mid-flight and corresponded with an increase (P < 0·05) in salivary cortisol from 5·4 µg/l (baseline) to 6·4 µg/l (loading). Additionally, rectal temperature increased (P < 0·05) from 38·61°C (baseline) to 39·33°C (mid-flight) and 39·72°C (post-flight). Helicopter travel did not affect search performance (P > 0·05). We found that α- and β-diversity measures of faecal microbiota were not affected (P > 0·05). Our data suggest that although helicopter travel may cause physiological changes that have been associated with stress in working dogs, it does not make an impact on their search performance or the stability of faecal microbiota.
Accurate models of X-ray absorption and re-emission in partly stripped ions are necessary to calculate the structure of stars, the performance of hohlraums for inertial confinement fusion and many other systems in high-energy-density plasma physics. Despite theoretical progress, a persistent discrepancy exists with recent experiments at the Sandia Z facility studying iron in conditions characteristic of the solar radiative–convective transition region. The increased iron opacity measured at Z could help resolve a longstanding issue with the standard solar model, but requires a radical departure for opacity theory. To replicate the Z measurements, an opacity experiment has been designed for the National Facility (NIF). The design uses established techniques scaled to NIF. A laser-heated hohlraum will produce X-ray-heated uniform iron plasmas in local thermodynamic equilibrium (LTE) at temperatures
eV and electron densities
. The iron will be probed using continuum X-rays emitted in a
diameter source from a 2 mm diameter polystyrene (CH) capsule implosion. In this design,
of the NIF beams deliver 500 kJ to the
mm diameter hohlraum, and the remaining
directly drive the CH capsule with 200 kJ. Calculations indicate this capsule backlighter should outshine the iron sample, delivering a point-projection transmission opacity measurement to a time-integrated X-ray spectrometer viewing down the hohlraum axis. Preliminary experiments to develop the backlighter and hohlraum are underway, informing simulated measurements to guide the final design.
Experiments on the National Ignition Facility show that multi-dimensional effects currently dominate the implosion performance. Low mode implosion symmetry and hydrodynamic instabilities seeded by capsule mounting features appear to be two key limiting factors for implosion performance. One reason these factors have a large impact on the performance of inertial confinement fusion implosions is the high convergence required to achieve high fusion gains. To tackle these problems, a predictable implosion platform is needed meaning experiments must trade-off high gain for performance. LANL has adopted three main approaches to develop a one-dimensional (1D) implosion platform where 1D means measured yield over the 1D clean calculation. A high adiabat, low convergence platform is being developed using beryllium capsules enabling larger case-to-capsule ratios to improve symmetry. The second approach is liquid fuel layers using wetted foam targets. With liquid fuel layers, the implosion convergence can be controlled via the initial vapor pressure set by the target fielding temperature. The last method is double shell targets. For double shells, the smaller inner shell houses the DT fuel and the convergence of this cavity is relatively small compared to hot spot ignition. However, double shell targets have a different set of trade-off versus advantages. Details for each of these approaches are described.
Genetically similar nulliparous Polled Hereford heifers from a closed pedigree herd were used to evaluate the effects of dietary protein during the first and second trimester of gestation upon foetal, placental and postnatal growth. Heifers were randomly allocated into two groups at 35 days after artificial insemination (35 days post conception (dpc)) to a single bull and fed high (15.7% CP) or low (5.9% CP) protein in the first trimester (T1). At 90 dpc, half of each nutritional treatment group changed to a high- or low-protein diet for the second trimester until 180 dpc (T2). High protein intake in the second trimester increased birth weight in females (P=0.05), but there was no effect of treatment upon birth weight when taken over both sexes. Biparietal diameter was significantly increased by high protein in the second trimester with the effect being greater in the female (P=0.02), but also significant overall (P=0.05). Placental weight was positively correlated with birth weight, fibroblast volume and relative blood vessel volume (P<0.05). Placental fibroblast density was increased and trophoblast volume decreased in the high-protein first trimester treatment group (P<0.05). There was a trend for placental weight to be increased by high protein in the second trimester (P=0.06). Calves from heifers fed the high-protein treatment in the second trimester weighed significantly more on all occasions preweaning (at 1 month (P=0.0004), 2 months (P=0.006), 3 months (P=0.002), 4 months (P=0.01), 5 months (P=0.03), 6 months (P=0.001)), and grew at a faster rate over the 6-month period. By 6 months of age, the calves from heifers fed high nutrition in the second trimester weighed 33 kg heavier than those fed the low diet in the second trimester. These results suggest that dietary protein in early pregnancy alters the development of the bovine placenta and calf growth to weaning.
Small < 10 m s−1 variations of radial velocity (RV) with multi-year periods in solar-type stars may be indistinguishable from the effects induced on lines by stellar activity cycles (Dravins 1985; Saar & Donahue 1997). Dravins (1992) recommended a resolving power R > 3 × 105 to measure accurately the subtle changes in the shapes of bisectors of photospheric absorption lines driven by changes of granular convection in slowly rotating dwarf stars. Butler et al. (1996) measure impressively small amplitudes of RVs by using echelle spectrographs that cover a broad spectrum. However, to cover a broad spectrum the resolving power is typically limited to < 7 × 104, and the necessary presence of the iodine absorption spectrum may make it difficult to measure convective line shifts contemporaneously with the RV time series. Furthermore, to reach an RV accuracy of ± 3 ms−1 the whole profile of each line is used, thus maximizing the possibility that changes in the shapes of the lines’ C-bisectors could induce an apparent variation of RV.
Dravins (1985) recommended the exclusive use of the steep flanks of photospheric absorption lines to minimize the effects of convection on apparent RV. McMillan et al. (1993, 1994) demonstrated that such RV measurements made with a Fabry-Perot etalon (FPE) interferometer in transmission can be stable in the presence of stellar line variations seen by other investigators whose measurements were not based exclusively on line flanks. Dravins also prescribed high resolving power, high signal-to-noise ratio, high instrumental contrast, and low instrumental wings to analyze the rest of the line profile for convectively-driven changes (Dravins 1978, 1987, 1992). A double- or multiple-pass FPE scanning whole line profiles can provide high R, high contrast, low wings, and a stable, symmetrical line spread function with small (portable) optics, although the low photon efficiency will restrict its use to a few carefully selected stars. The spectral classes of these stars should span the spectral classes of the stars being monitored by others for planets. We describe a possible implementation of this concept that has the potential for adequate photon flux: observing symbiotically through another instrument on a 6-m to 10-m class telescope.
We investigated a mixed outbreak of Legionnaires' disease (LD) and Pontiac fever (PF) at a military base to identify the outbreak's environmental source as well as known legionellosis risk factors. Base workers with possible legionellosis were interviewed and, if consenting, underwent testing for legionellosis. A retrospective cohort study collected information on occupants of the buildings closest to the outbreak source. We identified 29 confirmed and probable LD and 38 PF cases. All cases were exposed to airborne pathogens from a cooling tower. Occupants of the building closest to the cooling tower were 6·9 [95% confidence interval (CI) 2·2–22·0] and 5·5 (95% CI 2·1–14·5) times more likely to develop LD and PF, respectively, than occupants of the next closest building. Thorough preventive measures and aggressive responses to outbreaks, including searching for PF cases in mixed legionellosis outbreaks, are essential for legionellosis control.
We screened 176 healthy, adult (aged 18–55 years) US refugees from tuberculosis (TB)-endemic countries to evaluate whether cytokine responses to latent TB infection (LTBI) are modified in the setting of concurrent H. pylori and helminth infection. As measured by the Quantiferon-TB GOLD interferon-γ release assay, a total 38 (22%) subjects had LTBI, of which 28 (74%) also were H. pylori seropositive and/or helminth infected. Relative to ten subjects with LTBI only, 16 subjects with concurrent H. pylori infection had significantly elevated levels of IFN-γ, and nine subjects with both H. pylori and helminth infection had significantly elevated levels of IFN-γ, IL-2, IL-13, and IL-5. H. pylori is associated with enhanced IFN-γ responses to TB, even in the setting of concurrent helminth infection. Efficacy of TB vaccines may vary with the co-existence of these three infections in the developing world.
Fullerene chemistry is booming, but how the chemical reactions affect fullerene's materials properties has seldom been studied. We have investigated optical limiting behavior of a series of fullerene derivatives, polymers, and glasses and have observed the following structure-property relationships for optical limiting in the fullerene materials: (i) The fullerene polymers with aromatic and chlorine moieties, i.e., C60-containing polycarbonate (C60-PC), polystyrene (C60- PS), and poly(vinyl chloride) (C60-PVC), limit the 8-ns pulses of 532-nm laser light more effectively than does the parent C60; (ii) the fullerene polymers with carbonyl groups, i.e., C60- containing CR-39 (C60-CR-39) and poly(methyl methacrylate), (C60-PMMA), do not enhance C60's limiting power; and (iii) the aminated fullerene derivatives, i.e., HxC60 (NHR)x [R = -(CH2CH2O)2H (1), x = 11; -(CH2)6OH (2), x = 7; -cyclo-C6H11 (3), x = 11; -(CH2)3Si(OC2H5)3 (4), x = 4], and their sol-gel glasses, i.e., 1–3/SiO2 (physical blending) and 4-SiO2 (chemical bonding), show complex limiting responses, with 4(-SiO2) performing consistently better than 1-3(/SiO2). The fullerene glasses are optically stable and their optical limiting properties remainunchanged after being subjected to continuous attack by the strong laser pulses for ca. 1 h.
Multiple salmonellosis outbreaks have been linked to contaminated tomatoes. We investigated a multistate outbreak of Salmonella Typhimurium infections among 190 cases. For hypothesis generation, review of patients' food histories from four restaurant-associated clusters in four states revealed that large tomatoes were the only common food consumed by patients. Two case-control studies were conducted to identify food exposures associated with infections. In a study conducted in nine states illness was significantly associated with eating raw, large, round tomatoes in a restaurant [matched odds ratio (mOR) 3·1, 95% confidence interval (CI) 1·3–7·3]. In a Minnesota study, illness was associated with tomatoes eaten at a restaurant (OR 6·3, mid-P 95% CI 1·05–50·4, P=0·046). State, local and federal regulatory officials traced the source of tomatoes to Ohio tomato fields, a growing area not previously identified in past tomato-associated outbreaks. Because tomatoes are commonly eaten raw, prevention of tomato contamination should include interventions on the farm, during packing, and at restaurants.
Terrestrial digital photonic technology development will not satisfy all of the aerospace requirements since RF links are often required. Organic electro-optic devices are readily adaptable to RF functions into the 100 GHz and above frequency range. In addition to lossless links, they can be utilized for RF signal processing functions such as mixing, efficient harmonic generation and filtering. Devices can be densely packed with negligible cross talk.
In addition to the well known survivability requirements for space born applications (lifetime, reliability, thermal, shock, vibration and radiation hardness), issues of weight and power become dominant. Organic devices based on thin film technologies have an obvious potential advantage with respect to weight. However, integration with other optical and/or electronic components needs to be considered since connectors often dominated size and weight. Performance (when translated back into the electronic domain) scales as the optical power and device sensitivity squared. Thus, advances in device sensitivity can be nullified by increases in optical loss.
We studied the low frequency noise in top-contact pentacene Thin Film Transistors (TFTs). The relative spectral noise density of the drain current fluctuations SI/I2 had a form of 1/f noise in the measured frequency range 1Hz - 3.5kHz.
Our studies of the noise dependencies on the gate-source VGS and drain-source VDS voltages showed that the dependencies differed from those observed for conducting polymers and resembled those reported for crystalline Si n-MOSFETs.
To compare the device noise level with those of other devices and materials, we extracted the Hooge parameter α. In order to calculate the total number of carriers we used a model simulating the device DC characteristics, similar to that for amorphous Si TFTs. The extracted Hooge parameter was 0.04. For an organic material this is an extremely small value, which is three orders of magnitude smaller that the Hooge parameter values reported for conducting polymers and only several times higher than the values for amorphous Si TFTs.
The reactions of metal oxides including CuO, ZnO, V2O5, and PbO with 1,1,1,5,5,5-hexaflouro- 2,4-pentanedione (hfacH) were investigated. A hot-wall reactor was used to react hfacH with metal oxide powders to form sufficient quantities of volatile reaction products for characterization by Infrared Spectroscopy (IR), Elemental Analysis (EA), Nuclear Magnetic Resonance (NMR), Mass Spectroscopy (MS), Thermogravimetric Analysis and Differential Thermal Analysis (DTA). PbO, ZnO and CuO powders reacted rapidly at 200 °C to form the corresponding metal β-diketonates and V2O5 reacted to give OV(hfac)2. A differential cold-wall reactor was to used to measure etch rates of CuOx films as a function of temperature and hfacH partial pressure. AES and XPS analysis of the laser ablation deposited CuOx film annealed in an O2 atmosphere revealed that the film was composed of CuO and Cu2O. Etch rates of up to a I l.βm/min at hfacH partial pressure of 1 Torr at 270 °C were obtained. Laser induced etching of the same CuOx film with hfacH showed evidence of copper oxide removal.
Monocrystalline AlxGa1−xN(0001) (0.05 ≤ x ≤ 0.70) thin films, void of oriented domain structures and associated low-angle grain boundaries, have been grown at high temperatures via OMVPE directly on vicinal and on-axis α(6H)-SiC(0001) wafers using TEG, TEA and ammonia in a cold-wall, vertical, pancake-style reactor. The surface morphologies were smooth and die densities and distributions of dislocations were comparable to that observed in GaN(0001) films grown on high temperature A1N buffer layers. Double-crystal XRC measurements showed a FWHM value as low as 186 arc sec for the (0002) reflection. Spectra obtained via CL showed strong near band-edge emissions with FWHM values as low as 31 meV. The compositions of the AlxGa1−xN films were determined using EDX, AES and RBS and compared to the values of the bandgap as measured by spectral ellipsometry and CL emissions. A negative bowing parameter was found. Controlled n-type, Si-doping of AlxGa1−xN for x ≤ 0.4 has been achieved with net carrier concentrations ranging from ≈ 2 × 1017 cm−3 to 2 × 1019 cm−3. Acceptor doping with Mg for x < 0.13 was also successful.