T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically ...modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR.
T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19).
SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients.
CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.
Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow-up, NCT01492036.
National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.
We examine an eruptive sequence in late 2007 at Bezymianny Volcano to characterize the magmatic plumbing system and eruption-related seismicity. Earthquake locations reveal seismicity below and ...offset to the north of the volcano along a tectonic fault. Based on historical seismicity, the magma chamber is postulated to have a top at about 6
km depth. Minor dome explosions, large sub-plinian eruptions and dome collapses are analyzed using an automated event classification scheme. Low-frequency tremor, interpreted as gas escape, and low-frequency earthquakes are a dominant proportion of the energy released. We also examine multiplet earthquakes whose behavior during the study period changed significantly and systematically before the largest eruption, demonstrating the potential of tracking multiplets to assess changing conditions with the conduit.
We present a seismic model of the area beneath the Kluchevskoy volcano group (Kamchatka, Russia) based on the tomographic inversion of more than 66000 P and S arrival times from more than 5000 local ...earthquakes that occurred in 2004 and that were recorded by 17 permanent stations. Below a depth of 25 km beneath the Kluchevskoy volcano, we observed a very strong anomaly in the Vp/Vs ratio that reached as high as 2.2. This is a probable indicator of the presence of partially molten material with a composition corresponding to deeper mantle layers. The upper part of this anomaly at a depth of 25–30 km coincides with a cluster of strong seismicity that can be explained by strong mechanical stresses in the lowermost crust due to magma ascension, water release and/or phase transitions. In the crust, we observed regular seismicity clusters that link the mantle anomaly with the Kluchevskoy volcano and most likely indicate the paths of magma migration. Between depths of 8 and 13 km, we see several patterns of high Vp/Vs ratios, interpreted as intermediate‐depth magma storages. Directly below the Kluchevskoy volcano, we observed a shallow body of high Vp/Vs, which probably represents the activated magma chamber just beneath the volcano cone, which erupted in the beginning of 2005. The existence of three levels of magma storage, based on results of local earthquake tomography, may explain the variety of the lava composition and eruption regimes in different volcanoes of the Kluchevskoy group.
Key Points
We provide 3D tomographic model beneath the Kluchevskoy volcano group
We see the main magma source as an anomaly in the mantle with Vp/Vs >2.2
Intermediate magma chambers explain the diversity of eruption regimes
Explosive eruptions at steep-sided volcanoes may develop with complex precursor activity occurring in a poorly-understood magma plumbing system so that timelines and possible interactions with the ...geologic surrounding are often unresolved. Here we investigate the episode prior to the energetic December 20, 2017 eruption at Bezymianny volcano, Kamchatka. We compare degassing activity inferred from time-lapse camera images, seismicity and real-time seismic amplitude (RSAM) data derived from a temporary station network, as well as high-resolution InSAR displacement maps. Results show that the first changes can be identified in low-frequency seismicity and degassing at least 90 days before the eruption, while the first volcano-tectonic (VT) seismicity occurred 50 days before the eruption. Coinciding with significant changes of the RSAM, surface displacements affect the volcanic flanks at least 9 days prior to the eruption. Inversion modeling of the pre-eruptive surface deformation as well as deflation-type, co-eruptive surface changes indicate the presence of a shallow and transient reservoir. We develop a conceptual model for Bezymianny volcano initiating with deep seismicity, followed by shallow events, rockfalls, steaming and an inflating reservoir. The eruption is then associated with subsidence, caused by deflation of the same reservoir. This sequence and conceivable causality of these observations are providing a valuable contribution to our understanding of the shallow magma plumbing system beneath Bezymianny and may have relevance for volcano monitoring and early warning strategies at similar volcanoes elsewhere.
The Klyuchevskoy group of volcanoes (KGV) in Kamchatka includes three presently active volcanoes (Klyuchevskoy, Bezymianny, and Tolbachik) located close together in an area of approximately ...50 × 80 km. These three volcanoes have completely different compositions and eruption styles from each other. We have analyzed new data recorded by a temporary seismic network consisting of 22 seismic stations operated within the area of Tolbachik in 2014–2015 in conjunction with the data from the permanent network and the temporary PIRE network deployed at the Bezymianny volcano in 2009. The arrival times of the P and S waves were inverted using a local earthquake tomography algorithm to derive 3‐D seismic models of the crust beneath the KGV as well as accurate seismicity locations. High‐resolution structures beneath the Tolbachik volcanic complex were identified for the first time in this study. The tomography results reveal three different types of feeding system for the main KGV volcanoes. The basaltic lavas of the Klyuchevskoy volcano are supplied directly from a reservoir at a depth of 25–30 km through a nearly vertical pipe‐shaped conduit. The explosive Bezymianny volcano is fed through a dispersed system of crustal reservoirs where a lighter felsic material separates from the mafic component and ascends to the upper crust to form andesitic magma sources. For Tolbachik, low‐viscosity volatile‐saturated basalts ascend from two deep reservoirs following a system of fractures in the crust associated with the intersections of regional faults.
Plain Language Summary
The Klyuchevskoy group of volcanoes (KGV) in Kamchatka includes three presently active volcanoes (Klyuchevskoy, Bezymianny, and Tolbachik) located close together in an area of approximately 50 × 80 km. These three volcanoes are among the most active volcanoes in the world, and they have completely different compositions and eruption styles from each other. We have analyzed new data recorded by a temporary seismic network consisting of 22 seismic stations installed within the area of Tolbachik in 2014–2015 in harsh natural conditions. Based on these data, we have derived high‐resolution structures beneath the Tolbachik volcanic complex and surrounding areas. The tomography results reveal three different types of feeding system for the main KGV volcanoes. The basaltic lavas of the Klyuchevskoy volcano are supplied directly from a reservoir at a depth of 25–30 km through a nearly vertical pipe‐shaped conduit. The explosive Bezymianny volcano is fed through a dispersed system of crustal reservoirs where a lighter felsic material separates from the mafic component and ascends to the upper crust to form andesitic magma sources. For Tolbachik, low‐viscosity volatile‐saturated basalts ascend from two deep reservoirs following a system of fractures in the crust associated with the intersections of regional faults.
Key Points
A new crustal seismic model is constructed for Tolbachik and adjacent volcanoes
Seismicity beneath Klyuchevskoy reflects a straight conduit that brings magma directly from the mantle
The Bezymianny volcano is fed through separating felsic magma and volatiles from midcrustal sources
We develop a network‐based method for detecting and classifying seismovolcanic tremors. The proposed approach exploits the coherence of tremor signals across the network that is estimated from the ...array covariance matrix. The method is applied to four and a half years of continuous seismic data recorded by 19 permanent seismic stations in the vicinity of the Klyuchevskoy volcanic group in Kamchatka (Russia), where five volcanoes were erupting during the considered time period. We compute and analyze daily covariance matrices together with their eigenvalues and eigenvectors. As a first step, most coherent signals corresponding to dominating tremor sources are detected based on the width of the covariance matrix eigenvalues distribution. Thus, volcanic tremors of the two volcanoes known as most active during the considered period, Klyuchevskoy and Tolbachik, are efficiently detected. As a next step, we consider the daily array covariance matrix's first eigenvector. Our main hypothesis is that these eigenvectors represent the principal components of the daily seismic wavefield and, for days with tremor activity, characterize dominant tremor sources. Those daily first eigenvectors, which can be used as network‐based fingerprints of tremor sources, are then grouped into clusters using correlation coefficient as a measure of the vector similarity. As a result, we identify seven clusters associated with different periods of activity of four volcanoes: Tolbachik, Klyuchevskoy, Shiveluch, and Kizimen. The developed method does not require a priori knowledge and is fully automatic; and the database of the network‐based tremor fingerprints can be continuously enriched with newly available data.
Key Points
A network‐based method for the automatic detection and classification of seismovolcanic tremors is developed
The developed clustering algorithm automatically identifies seven clusters associated with different periods of activity of four volcanoes
The developed method does not require a priori knowledge, is fully automatic, and can be updated continuously with newly available data
Interferometric synthetic aperture radar (InSAR) images reveal a pre-eruption deformation signal at Kizimen volcano, Kamchatka, Russia, where an ongoing eruption began in mid-November, 2010. The ...previous eruption of this basaltic andesite-to-dacite stratovolcano occurred in 1927–1928. InSAR images from both ascending and descending orbital passes of Envisat and ALOS PALSAR satellites show as much as 6cm of line-of-sight shortening from September 2008 to September 2010 in a broad area centered at Kizimen. About 20cm of opening of a nearly vertical dike provides an adequate fit to the surface deformation pattern. The model dike is approximately 14km long, 10km high, centered 13km beneath Kizimen, and strikes NE–SW. Time-series analysis of multi-temporal interferograms indicates that (1) intrusion started sometime between late 2008 and July 2009, (2) continued at a nearly constant rate, and (3) resulted in a volume expansion of 3.2×107m3 by September 2010, i.e., about two months before the onset of the 2010 eruption. Earthquakes located above the tip of the dike accompanied the intrusion. Eventually, magma pressure in the dike exceeded the confining strength of the host rock, triggering the 2010 eruption. Our results provide insight into the intrusion process that preceded an explosive eruption at a Pacific Rim stratovolcano following nearly a century of quiescence, and therefore have implications for monitoring and hazards assessment at similar volcanoes elsewhere.
► InSAR images reveal pre-eruption deformation at Kizimen volcano before 2010 eruption. ► A vertical dike of 14km by 10km at ~13km depth fits to the deformation pattern. ► Magma intrusion started sometime between late 2008 and July 2009. ► Intrusion rate was about constant till 09/2010, 2months before the 2010 eruption. ► Earthquakes located above the rising tip of the dike accompanied the intrusion.
Digital pixel test structures implemented in a 65 nm CMOS process Aglieri Rinella, Gianluca; Andronic, Anton; Antonelli, Matias ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
11/2023, Letnik:
1056
Journal Article
Recenzirano
Odprti dostop
The ALICE ITS3 (Inner Tracking System 3) upgrade project and the CERN EP R&D on monolithic pixel sensors are investigating the feasibility of the Tower Partners Semiconductor Co. 65nm process for use ...in the next generation of vertex detectors. The ITS3 aims to employ wafer-scale Monolithic Active Pixel Sensors thinned down to 20–40µm and bent to form truly cylindrical half barrels. Among the first critical steps towards the realisation of this detector is to validate the sensor technology through extensive characterisation both in the laboratory and with in-beam measurements. The Digital Pixel Test Structure (DPTS) is one of the prototypes produced in the first sensor submission in this technology and has undergone a systematic measurement campaign whose details are presented in this article.
The results confirm the goals of detection efficiency and non-ionising and ionising radiation hardness up to the expected levels for ALICE ITS3 and also demonstrate operation at ＋20°C and a detection efficiency of 99% for a DPTS irradiated with a dose of 10151MeV neq cm-2. Furthermore, spatial, timing and energy resolutions were measured at various settings and irradiation levels.
In this work the initial performance studies of the first small monolithic pixel sensors dedicated to charged particle detection, called CE-65, fabricated in the 65nm TowerJazz Panasonic ...Semiconductor Company are presented. The tested prototypes comprise matrices of 64×32 square analogue-output pixels with a pitch of 15μm. Different pixel types explore several sensing node geometries and amplification schemes, which allows for various biasing voltage of the detection layer and hence depletion conditions and electric field shaping. Laboratory tests conducted with a 55Fe source demonstrated that the CE-65 sensors reach equivalent noise charge in the 15 to 25e− range and excellent charge collection efficiencies. Charge sharing is substantial for standard diodes, but can be largely suppressed by modifying their design. Depletion of the thin sensitive layer saturates at a reverse diode bias of about 5 V.
Gorely is an active volcano located 75 km from Petropavlovsk-Kamchatsky, Kamchatka. In 2010–2015, it exhibited strong activity expressed by anomalously high gas emission. In 2013–2014, we deployed a ...temporary network consisting of 20 temporary seismic stations that operated for one year. We selected 333 events with 1613 P-wave and 2421 S-wave arrival times to build the first tomographic model of this volcano. The seismic model was carefully verified using a series of synthetic tests. Our tomographic model provides a mechanism for volatile feeding of Gorely. An unexpected feature of the model was low Vp/Vs ratios; below 1.4 in some parts. One reason for such low Vp/Vs ratios is gas contamination due to magma degassing. In the central part of the model, directly underneath the Gorely crater, we observe a 2.5 km wide and 1.5 km thick seismic anomaly with a very high Vp/Vs ratio of up to 2. This may represent a magma reservoir with a high melt and/or volatile content. The upper limit of this anomaly, 2.5 km below the surface, may indicate the degassing level, which coincides with the most intense seismicity. Below this reservoir, we observe another columnar high Vp/Vs ratio anomaly. This can be interpreted as a conduit bringing magma and fluids from deeper sources.
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