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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.
Supernovae are classified as type I and type II and further subdivided into Ia, Ib, Ic, II-P, II-L, and IIb. The origin of this observational diversity has not been well understood. The recent nearby supernovae SN 1993J and SN 1994I have provided particularly useful material to clarify the supernova — progenitor connection. For a progenitor of type IIb supernova 1993J, we propose that merging of two stars in a close binary is responsible for the formation of a thin H-rich envelope. As a progenitor of type Ic supernova 1994I, we propose a bare C+O star that has lost both its H and He envelope after a common-envelope phase. By generalizing these scenarios, we show that common-envelope evolution in massive close binary stars leads to various degrees of stripping off of the envelope of a massive star. This naturally leads to an explanation of the origin of type II-L, IIn, IIb, Ib, and Ic in a unified manner. The binary hypothesis to explain the diversity of supernovae can be substantiated with new information on SN IIb 1993J and SN Ic 1994I. Model light curves are compared with observations. Since extensive mass loss is essential for the binary scenario, circumstellar interactions are examined for comparison with X-ray observations.
We discuss the properties of the very energetic Type Ic supernovae (SNe Ic) 1998bw and 1997ef, and of Type IIn supernova (SN IIn) 1997cy. SNe Ic 1998bw and 1997ef are characterized by their large luminosity and very broad spectral features. Their observed properties can be explained if they are very energetic SN explosions (EK ≳ 1 × 1052 erg), originating probably from the core collapse of the bare C+O cores of massive stars (~ 30–40M⊙). At late times, both the light curve and the spectra suggest that the explosion may have been asymmetric; this may help us understand the claimed connection with GRBs. Type IIn SN 1997cy is even more luminous than SN 998bw, and the light curve declines more slowly than the 56Co decay. We model such a light curve with circumstellar interaction, which requires the explosion energy of ~ 5 × 1052 erg. Because these kinetic energies of explosion are much larger than in normal core-collapse SNe, we call objects like these SNe “hypernovae”.
This study evaluated the structural and morphological differences between human and bovine primary root canals. Primary human maxillary central incisors (H) (n=9) and primary bovine incisors (B) (n=9) were selected. The roots were sectioned in the vestibular-lingual direction, planed and delimited in cervical, middle, and apical thirds. Tubule density (number of tubules per mm2) and diameter were analyzed by scanning electron microscopy (1,000 and 5,000×) using Image J 1.47 software. Data were submitted to two-way repeated measures ANOVA and Tukey tests (α=0.05). The highest tubule density was observed for B (28.527±1.717 mm2) compared with H (15.931±0.170 mm2) (p<0.01). Regarding root thirds, the cervical third presented a greater tubule density (26.417±11.654 mm2) than the apical third (17.999±5.873 mm2). The diameter of the dentin tubules was not different for cervical (3.50±0.08 µm), middle (3.45±0.30 µm) and apical thirds (3.42±0.33 µm) and substrate (H—3.29±0.14 µm; B—3.63±0.06 µm). It could be concluded that: (1) the radicular dentin structure of human and bovine primary teeth and root thirds differ in terms of the tubule density; (2) the radicular dentin morphology of human and bovine primary teeth and root thirds are similar in terms of the diameter of the dentin tubules.
US public health laboratories began reporting Escherichia coli O157 isolates to CDC in 1996. We describe temporal and geographical patterns of isolates reported from 1996 to 2011 and demographics of persons whose specimens yielded isolates. We calculated annual E. coli O157 isolation rates/100 000 persons by patient's state of residence, county of residence, age, and sex using census data. The average annual isolation rate was 0·84. The average isolation rate in northern states (1·52) was higher than in southern states (0·43). Counties with ⩾76% rural population had a lower isolation rate (0·67) than counties with ⩽25%, 26–50%, and 51–75% rural populations (0·81, 0·92, and 0·81, respectively). The highest isolation rate (3·19) was in children aged 1–4 years. Infections were seasonal with 49% of isolates collected during July to September. Research into reasons for higher incidence in northern states and for seasonality could guide strategies to prevent illnesses.
Vibrio vulnificus (Vv) can result in severe disease. Although pre-existing liver disease is a recognized risk factor for serious infection, the relative importance of other comorbidities has not been fully assessed. We analysed reports of Vv infections submitted to CDC from January 1988 to September 2006 in order to assess the role of pre-existing conditions contributing to severe outcomes. A total of 1212 patients with Vv infection were reported. Only patients with liver disease [adjusted odds ratio (aOR) 5·1)] were more likely to become septic when exposure was due to contaminated food. Patients with liver disease (aOR 4·1), a haematological disease (aOR 3·2), or malignancy (aOR 3·2) were more likely to become septic when infection was acquired via a non-foodborne exposure. As such, patients with these pre-existing medical conditions should be advised of the risk of life-threatening illness after eating undercooked contaminated seafood or exposing broken skin to warm seawater.
We report the formation and optical properties of site-controlled InAs/GaAs quantum dots (QDs) embedded in GaAs nanowires (NWs) by selective metalorganic chemical vapor deposition for application to single photon sources. InAs/GaAs QD-in-NWs with various InAs thicknesses are realized on patterned GaAs(111)B substrates in the form of InAs/GaAs heterostructures and identified by structural analyses using scanning transmission electron microscopy and photoluminescence characterization. Sharp excitonic emission peaks at 10 K from single QD-in-NWs with the narrowest exciton linewidth of 87 μeV are observed. Light emission from the single QD-in-NW shows photon antibunching which evidences single photon emission from high-quality QD-in-NWs.
By using electric-field-induced second-harmonic generation (EFISHG) measurement, we analyzed photovoltaic effect of two-layer solar cells (indium zinc oxide/pentacene/C60/Al). Results evidently showed that negative and excessive charges Qs accumulated at the two-layer interface under illumination, e.g., Qs =-1.7×10-9 C/cm2 at 0.05 mW/cm2 and –3.6×10-9 C/cm2 at 0.5 mW/cm2, while a short-circuit current flowed. The open-circuit voltage changed in accordance with accumulation charge Qs, and finally saturated. Modeling that accumulated negative charge is a source of space charge field and directly effects on the electrostatic energy stored in OSCs, dependence of the open voltage on the accumulated charge Qs was explained.
We studied antiphase domain (APD) growth and lamellar structure formation during isothermal annealing of Ti-39at%Al single crystals at α2+γ dual phase temperature after quenching from α single phase state, intending to obtain a APD/lamellae mixed microstructure and to examine whether such a microstructure provides a strength higher than that obtained only by refining lamellar structure. The effect of plastic deformation prior to the annealing was also examined expecting a acceleration of γ lamellae formation through a preferential nucleation of γ-plates at dislocations. The lower was the annealing temperature, the smaller both the APD size and the lamellar spacing at the moment of a homogeneous lamellar structure formation tended to be, although naturally both the APD growth and the γ lamellae formation were slower. However, the APD size in the homogeneous lamellar structure was no smaller than 400 nm. A structure with finer APDs and finer lamellar structure was obtained by deforming the crystal before annealing since the lamellar structure formation was accelerated and the time for APD growth before the lamellar structure formation was shortened. For instance, a structure with an average lamellar spacing of 88 nm and an average APD size of 214 nm was obtained by deforming the crystals to 10 % plastic strain and subsequently annealing at 1073 K for 1×104 s, while no γ plate was obtained only by such an annealing without deformation.
A novel characterization method is applied to study the evolution of microstructures during densification of silicon nitride ceramics. This characterization method involves an immersion liquid for making green and sintered bodies transparent, and a subsequent direct optical microscopic examination. Granules were prepared with the spray drying processand formed into green bodies by CIP. After sintering at various temperatures, the specimens were examined for microstructural evolution. Large pores were located at the center and boundary regions of granules left in the green bodies; they were not removed by densification and resulted in large pores in the sintered body, possibly forming fracture origin in ceramics.
As higher levels of reliability are sought, it will become increasingly important to understand the relationship between the adhesive formulation and its bonded substrate. Johnson Matthey has been addressing this need by using molecular modeling to simulate the physical effects of adhesive components on properties such as adhesion, surface spread or bleed, and underfill flow. By using a molecular modeling method as opposed to a continuum calculation, the individual components of an adhesive may be theoretically manipulated without pre-determination of properties or property effects. The potential utility of the technique lies in the prediction or confirmation of property trends when different components or processes are used. Additionally, the molecular scale helps to gain insight of the interfacial contribution to performance.
We have investigated the flat-band voltage (VFB) shifts of tantalum nitride gate MOS capacitors prepared by two methods. One is CVD-tantalum nitride (CVD-TaN) deposited by the chemical vapor deposition technique using Ta[NC(CH3)2C2H5][N(CH3)2]3 as a precursor, and the other one is sputtered tantalum nitride (sp-TaN) electrodes deposited by reactive DC magnetron sputtering. In the case of the CVD-TaN electrodes, the effective work function estimated from the relationship between VFB and the equivalent oxide thickness (EOT) of the MOS capacitors was about 4.4eV after post metallization annealing (PMA) at 400°C, and shifted to the mid-gap after PMA at 950°C. Moreover, the VFB values of MOS capacitors with sp-TaN electrodes also showed the same behavior after PMA. This shift is mainly dependent on the PMA temperature, regardless of the deposition method used. Similar VFB shifts induced by PMA were also observed in sp-TaN/ Al2O3/ SiO2/ p-Si and sp-TaN/ TaOx/ SiO2/ p-Si capacitors. However, in the case of the sp-TaN/ TaOx/ SiO2/ p-Si capacitors, the VFB shift was also observed when the PDA temperature after the TaOx deposition was 800°C and the PMA temperature after the TaN deposition was only 400°C. These results strongly suggest that this VFB shift caused by the PMA originates from a thin interfacial oxide layer between the TaN gate electrode and the dielectrics. Therefore, the maximum processing temperature after gate electrode deposition is important in order to control the threshold voltage of tantalum nitride gate MOSFETs.
A multistate outbreak of Escherichia coli O157:H7 infections occurred in the USA in November–December 2006 in patrons of restaurant chain A. We identified 77 cases with chain A exposure in four states – Delaware, New Jersey, New York, and Pennsylvania. Fifty-one (66%) patients were hospitalized, and seven (9%) developed haemolytic uraemic syndrome; none died. In a matched analysis controlling for age in 31 cases and 55 controls, illness was associated with consumption of shredded iceberg lettuce [matched odds ratio (mOR) 8·0, 95% confidence interval (CI) 1·1–348·1] and shredded cheddar cheese (mOR 6·2, CI 1·7–33·7). Lettuce, an uncooked ingredient, was more commonly consumed (97% of patients) than cheddar cheese (84%) and a single source supplied all affected restaurants. A single source of cheese could not explain the regional distribution of outbreak cases. The outbreak highlights challenges in conducting rapid multistate investigations and the importance of incorporating epidemiological study results with other investigative findings.
Infection by Listeria monocytogenes in pregnant women may result in fetal loss or invasive disease in the newborn. We examined listeriosis cases reported through the U.S. Listeria Initiative during 2004–2007. Cases were classified as pregnancy-associated if illness occurred in a pregnant woman or an infant aged <28 days. Of 758 reported Listeria cases, 128 (16·9%) were pregnancy-associated. Maternal infection resulted in four neonatal deaths and 26 (20·3%) fetal losses. Invasive illnesses in newborns (n=85) were meningitis (32·9%) and sepsis (36·5%). Pregnant women with Listeria were more likely to report Hispanic ethnicity (52·8% vs. 25·6%, respectively; OR 3·3 95% CI 2·2–4·8) than mothers giving live birth in the USA during 2005 and were more likely to report consumption of Mexican-style cheese (OR 2·6, 95% CI 1·6–4·2) than were non-pregnant patients with Listeria infection. Pregnant woman comprised a considerable proportion of reported listeriosis cases. Further declines in pregnancy-associated listeriosis will require education about avoiding high-risk foods, and continued regulatory and industry efforts to decrease Listeria in foods.
Human bocavirus (HBoV) was recently identified in respiratory samples from patients with acute respiratory infections and has been reported in different regions of the world. To the best of our knowledge, HBoV has never been reported in respiratory infections in Brazil. Nasopharyngeal aspirates were collected from patients aged <5 years hospitalized in 2005 with respiratory infections in Ribeirão Preto, southeast Brazil, and tested by polymerase chain reaction (PCR) for HBoV. HBoV-positive samples were further tested by PCR for human respiratory syncytial virus, human metapneumovirus, human coronaviruses 229E and OC43, human influenza viruses A and B, human parainfluenza viruses 1, 2 and 3, human rhinovirus and human adenovirus. HBoV was detected in 26/248 (10·5%) children of which 21 (81%) also tested positive for other respiratory viruses. Despite the high rates of co-infections, no significant differences were found between HBoV-positive patients with and without co-infections with regard to symptoms.
“Stand-support sintering”, that is supporting the load of the sinter cake with bars or
plates attached to pallets, has been developed and applied practically to the sintering
machines in Kimitsu works, Nippon Steel. The stands start to support the load of the sinter
cake just after the top layer is melted and starts to solidify. Shrinkage is stopped
and the gas flow rate is increased when the stands start to support the load of the
sinter cake. It was found that sintering time was shortened and productivity was improved in
actual sintering machines.
In an ion-beam–inhomogeneous-plasma system, when the drift frequency
ω* exceeds a harmonic of the ion cyclotron frequency nωci, ion cyclotron harmonic
waves are excited via the plasma inhomogeneity. These waves are strongly enhanced
by ion-beam injection parallel to the magnetic field. As the plasma inhomogeneity
is increased, the number of unstable modes increases as does their amplitude. Ion
cyclotron harmonic waves with frequencies up to 4ωci are observed experimentally;
at least five modes become unstable, and these unstable waves have different az-imuthal
mode numbers l = 1 or 2. The dispersion relations of observed multiple ion
cyclotron harmonic waves agree well with the theoretical ones, taking into account
the plasma inhomogeneity and the ion beam.
Rhnull is a syndrome serologically characterized by
deficiency of all Rh antigens on human red
blood cells. Rhnull is divided into two types: regulator and
amorph. Recently, Cherif-Zahar et al.
proposed that the RHAG gene encoding the Rh50 glycoprotein is
a candidate for inducing regulator
type Rhnull. We investigated both the RH and RHAG
genes in an Rhnull individual. The reticulocytes
from the propositus had RHD, RHcE, and RHCe
transcripts without any mutation. However, the
sequence analysis of RHAG cDNA showed a deletion of 122 bp from
nucleotide 946 to 1067. This
deletion was revealed to be due to a homozygous splicing mutation, which
is a single base
substitution at the consensus sequence of the splicing acceptor site
(AG→AT). The mutation
appeared to break the ‘GT-AG’ splicing rule and to cause
122 bp exon skipping accompanied by a
frameshift. This study confirms that the RHAG gene is the
most likely candidate for the ‘regulator’
gene of Rhnull cases.
To describe control of endemic and outbreak-related methicillin-resistant Staphylococcus aureus (MRSA) at two affiliated hospitals.
Prospective surveillance of patients with MRSA. Disposable gloves were used by all staff having direct contact with the affected patient or his immediate environment, and patient isolates were typed by pulsedfield gel electrophoresis (PFGE) of genomic DNA. Surveillance and PFGE typing were used concurrently to identify possible nosocomial outbreaks, confirm or refute cross-infection, and support a need for additional outbreak control interventions.
A university hospital (Hospital A) and a university-affiliated public hospital (Hospital B).
Patients with MRSA colonization or infection over an 18-month interval (June 1993-November 1994).
Proper handwashing and gloving practices were reemphasized with staff following confirmation of outbreaks.
Hospital A had 60 community-acquired and 48 nosocomial cases of MRSA. Two small outbreaks (affecting a total of seven patients) and two pseudo-outbreaks were identified. Hospital B had 36 community-acquired and 22 nosocomial cases of MRSA. Only one outbreak affecting five patients occurred. All outbreaks ended shortly after staff meetings that emphasized ongoing and extremely careful handwashing and gloving when caring for identified patients. The majority of nosocomial cases at both hospitals were not related epidemiologically or had isolates with unique PFGE types. Pseudo-outbreaks were confirmed by demonstrating that isolates from epidemiologically related cases (by time and clinical service or hospital unit) had different PFGE types. Hospital A cases had 39 different PFGE types, and Hospital B cases had 31 different PFGE types.
MRSA in hospitals, including outbreaks identified by prospective surveillance and confirmed by PFGE typing, can be controlled by minimal special precautions and interventions. This is possible despite the continuous admission of patients with MRSA from the community. PFGE typing is useful to confirm outbreaks and pseudo-outbreaks, demonstrate differences among epidemiologically unrelated isolates, and substantiate the efficacy of MRSA control programs within hospitals.
Microstructure evolution was studied in silicon nitride ceramics by a novel characterization method, and its relevance to the strength was discussed. The characterization method involves an immersion liquid for making green and partially sintered bodies transparent, and a subsequent direct optical microscopic examination. Granules for compaction process were prepared with the spray-drying process and were found to contain pores or deep dimples. Green bodies formed by CIP with these granules contain regularly arrayed pores at the center of granules and also crack-like voids at the boundaries of granules. These pores were preserved in the sintering process and resulted in large pores in the sintered body. They behave as fracture origin in ceramics and reduce the fracture strength. The Weibull modulus was high due to the presence of uniformly distributed pores.
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