Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell ...therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
cells/kg range, 0.07 to 2.1 × 10
) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval CI, 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
Nanoscale metal–organic frameworks (nanoMOFs) are promising porous nanomaterials for diverse applications, such as catalysis, imaging, functional membranes, and drug delivery. At the nanoscale, the ...size of materials is critical for their properties and utility. Herein, a straightforward and convenient strategy is developed for size precisely controlled synthesis of nanoMOFs. Unlike other approaches, this strategy can directly give nanoMOFs of predicable sizes within a wide range without the time consuming trial‐and‐error process and without the addition of additives. In this approach, the preciseness of size control is ensured by the separated and controlled nucleation and growth. The size controlled synthesis of 9 kinds of most widely studied nanoMOFs confirms the versatility of this strategy. More importantly, this approach can be utilized for scale‐up synthesis of nanoMOFs with the same precise size control.
About the size of it: Homogeneous nanoscale metal–organic frameworks (nanoMOFs) of predicable size within a wide range are synthesized. The precise size control is ensured by the controlled nucleation and controlled growth in this strategy. This strategy is applicable for scale‐up synthesis of nanoMOFs with precise size control.
Multi‐component MOFs contain multiple sets of unique and hierarchical pores, with different functions for different applications, distributed in their inter‐linked domains. Herein, we report the ...construction of a class of precisely aligned flexible‐on‐rigid hybrid‐phase MOFs with a unique rods‐on‐octahedron morphology. We demonstrated that hybrid‐phase MOFs can be constructed based on two prerequisites: the partially matched topology at the interface of the two frameworks, and the structural flexibility of MOFs with acs topology, which can compensate for the differences in lattice parameters. Furthermore, we achieved domain selective loading of multiple guest molecules into the hybrid‐phase MOF, as observed by scanning transmission electron microscopy–energy‐dispersive X‐ray spectrometry elemental mapping. Most importantly, we successfully applied the constructed hybrid‐phase MOF to develop a dual‐drug delivery system with controllable loading ratio and release kinetics.
A class of precisely aligned flexible‐on‐rigid hybrid‐phase MOFs were synthesized by the heteroepitaxial growth of acs‐topology MOF on the surface of fcu‐topology MOF. Domain‐selective loading of multiple guests into the hybrid‐phase MOFs was achieved by size‐selective encapsulation or selective binding. A dual‐drug delivery system with controllable loading ratio and release kinetics was developed based on the hybrid‐phase MOF.
The Mesozoic Western Pacific subduction system significantly impacted the North China and South China blocks along the East Asian continental margin and influenced the tectonic, magmatic, ...metallogenic and geomorphic evolution of the region. However, the dynamics and impact on the zone along the East Asian ocean-continent connection zone remain debated. Here we provide a comprehensive synthesis of the state-of-the-art information from deformation analysis, magmatism, geochronology, tomography and other fields from this region. We evaluate first the pre-Yanshanian (pre-Jurassic) final assembly of blocks and the Late Triassic formation of the unified continental margin in East China. We then focus on the Jurassic and Cretaceous geological processes in the East Asian ocean-continent connection zone. The temporal and spatial evolution of structural propagation, sedimentary depocentre, age zonation and migration of magmatism, as well as the large-scale tectono-morphological inversion in the Earth surface system combined with deep processes, are probed. In the early Yanshannian Period (Early and Middle Jurassic, 200–160 Ma), the destruction of the North China Craton (NCC) was mainly affected by the westward early-stage layered rollback, and stepwise delamination and thinning of its continental lithosphere, resulting in the early Yanshanian westward migration of tectonism and magmatism. Coevally, the combined effect of the closure of the Mongal-Okhotsk Ocean to the north and the subduction of the Bangong-Co- Nujiang Ocean to the south imparted an overall compressional setting in the East Asian Ocean-Continent Connection Zone (EAOCCZ). The centres of asthenospheric upwelling and mantle extrusion at depth continued to migrate eastward, driving the eastward lithospheric thinning with periodic and alternating extension and compression. The South China Block experienced a westward flat subduction during the early Yanshanian Period, resulting in the westward propagation of deformation and magmatism, followed by late two-stage delamination to induce the eastward tectono-magmatism. The difference in tectono-magmatic styles between the North China and South China blocks is a result of the different mechanisms and syles of the deep delamination processes under the superconvergence regime of the East Asian and adjacent plates. Especially delamination under North China generated the northwestward layered and fractured subcontinental lithospheric mantle, whereas under the eastern South China Block, were the oceanic lithospheric mantle of the Paleo- Pacific Plate that underwent flat subduction, or continental garnet peridotite mantle. In the middle Yanshanian Period (Late Jurassic to early Early Cretaceous, 160–125 Ma), the EAOCCZ underwent escape tectonics to form some basins related to strike slip faulting. Generally the extensional basins in the tails of the triangular-shaped escape blocks are perpendicular to the extrusion direction. The transtensional or transpressional basins are controlled by the strike slip faults distributed on both sides of the triangular block, and the flexural basins occur in front. In the late Yanshanian Period (late Early Cretaceous-Late Cretaceous, 125–65 Ma), the Paleo-Pacific (Izanagi) Plate subducted NNW-ward beneath the Eurasian continent, and the subduction angles changed gradually following eastward mantle extrusion induced by the closure of the Okhotsk Ocean to the north and Bangong-Nujiang Ocean to the south, as well as the rollback and subduction retreat of the Paleo-Pacific Plate to the east. The EAOCCZ gradually experienced lithospheric collapse and the formation of metamorphic core complexes, as well as obvious landscape reversal. During 70–45 Ma, the Izanagi-Pacific Ridge subducted beneath the EAOCCZ to induce wide uplift resulting in the formation of the Cenozoic dextral transtension-related basins.
The formation of lateral branches has an important and fundamental contribution to the remarkable developmental plasticity of plants, which allows plants to alter their architecture to adapt to the ...challenging environment conditions. The Gibberellin (GA) phytohormones have been known to regulate the outgrowth of axillary meristems (AMs), but the specific molecular mechanisms remain unclear. Here we show that DELLA proteins regulate axillary bud formation by interacting and regulating the DNA‐binding ability of SQUAMOSA‐PROMOTER BINDING PROTEIN LIKE 9 (SPL9), a microRNA156‐targeted squamosa promoter binding protein‐like transcription factor. SPL9 participates in the initial regulation of axillary buds by repressing the expression of LATERAL SUPPRESSOR (LAS), a key regulator in the initiation of AMs, and LAS contributes to the specific expression pattern of the GA deactivation enzyme GA2ox4, which is specifically expressed in the axils of leaves to form a low‐GA cell niche in this anatomical region. Nevertheless, increasing GA levels in leaf axils by ectopically expressing the GA‐biosynthesis enzyme GA20ox2 significantly impaired axillary meristem initiation. Our study demonstrates that DELLA‐SPL9‐LAS‐GA2ox4 defines a core feedback regulatory module that spatially pattern GA content in the leaf axil and precisely control the axillary bud formation in different spatial and temporal.
As an important agronomic trait, lateral branches closely related to crop yield. In this study, we demonstrated that phytohormone gibberellin represses the axillary bud formation through enhancing the activity of transcription factor SPL9 to repress the expression of LAS that is a key regulator in the initiation of axillary buds.
Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in ...patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 x 10.sup.6 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced greater than or equal to 1 adverse events (AEs). Grade greater than or equal to 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade greater than or equal to 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285. Keywords: Multiple myeloma, Chimeric antigen receptor therapy, B cell maturation antigen, Safety, Efficacy
Fundamental understanding of the dynamic behaviors at the electrochemical interface is crucial for electrocatalyst design and optimization. Here, we revisit the oxygen reduction reaction mechanism on ...a series of transition metal (M = Fe, Co, Ni, Cu) single atom sites embedded in N-doped nanocarbon by ab initio molecular dynamics simulations with explicit solvation. We have identified the dissociative pathways and the thereby emerged solvated hydroxide species for all the proton-coupled electron transfer (PCET) steps at the electrochemical interface. Such hydroxide species can be dynamically confined in a "pseudo-adsorption" state at a few water layers away from the active site and respond to the redox event at the catalytic center in a coupled manner within timescale less than 1 ps. In the PCET steps, the proton species (in form of hydronium in neutral/acidic media or water in alkaline medium) can protonate the pseudo-adsorbed hydroxide without needing to travel to the direct catalyst surface. This, therefore, expands the reactive region beyond the direct catalyst surface, boosting the reaction kinetics via alleviating mass transfer limits. Our work implies that in catalysis the reaction species may not necessarily bind to the catalyst surface but be confined in an active region.
A robust cluster-based Eu-MOF has been created by a tetrazolyl-carboxyl linker, which shows great chemical and thermal stability and multiple functions of fluorescent sensor for the detection of ...antibiotics (MDZ, DMZ) and pesticides (DCN).
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•A robust cluster-based Eu-MOF as a fluorescence probe.•Resistance to water, organic solvents and wide pH value range.•Selective detection of MDZ, DMZ and DCN with low detection limit, rapid response.•Detected MDZ and DMZ in calf serum and sensed DCN in lake water.•Combining experiments and calculations to study the sensing mechanism.
As a hot issue of global concern, the abuse of organic pollutants, including pesticides and antibiotics poses a great threat to the human health and ecological environment. Effective and accurate detection of these species is of profound significance in many fields. In this work, a novel 3D metal-organic framework (MOF) Eu2(dtztp)(OH)2(DMF)(H2O)2.5·2H2O (1) was solvothermally synthesized. 1 is a three-dimensional framework based on tetranuclear Eu4(μ3-OH)4(μ2-OH2)8+ clusters, and reveals the great chemical stability and excellent tolerance in water and organic solvents. The MOF also shows strong fluorescence that was undisturbed by the pH in aqueous water (pH = 3–12). Importantly, 1 can quickly detect metronidazole (MDZ) and dimetridazole (DMZ) antibiotics as well as 2,6-dichloro-4-nitroaniline (DCN) pesticide in water with good recyclability and low detection limit. MDZ, DMZ and DCN were also successfully detected in calf serum and lake water, respectively. The mechanism of fluorescence quenching was disclosed through the combination of experiments and density functional theory calculations.
Different from isolated metal atoms and large metal nanoparticles (NPs), supported metal clusters (SMCs) possess distinct geometric and electronic structures and thus exhibit enhanced activity and ...designated selectivity in catalysis. So far, with the development in synthetic methodologies and characterization techniques, SMCs with fine structures could be constructed and well-defined at the atomic level. In addition, based on computational modeling of SMCs, theoretical calculations corroborated well with experimental results, providing in-depth insights into the structure–property relationship for SMCs in catalysis. In this Review, classic synthetic strategies and key characterization techniques of SMCs are summarized. Subsequently, the applications of SMCs in important catalytic reactions based on recent studies are discussed, including aerobic oxidation, hydrogenation, dehydrogenation, water–gas shift (WGS) reaction, and photocatalytic reactions. In particular, the importance of the cluster size-effect and metal–support interactions in determining the catalytic performance of SMCs is highlighted. Lastly, challenges and prospects in SMCs’ catalysis are illustrated.
DNA origami has been widely investigated as a template for the organization of various functional elements, leading to potential applications in many fields such as biosensing, nanoelectronics, and ...nanophotonics. However, the synthesis of inorganic nonmetallic nanomaterials with predesigned patterns using DNA origami templates has seldom been explored. Here, a novel method is reported to site‐specifically synthesize silica nanostructures with designed patterns on DNA origami templates. The molecular dynamic simulation confirms that the positively charged silica precursors have a stronger electrostatic affinity to protruding double‐stranded DNA (dsDNA) than DNA origami surfaces. The work describes a novel strategy to fabricate silica nanostructures with nanoscale precision. Moreover, the site‐specific silicification of DNA nanoarchitectures expands the scope of customized synthesis of inorganic nonmetallic nanomaterials.
Arbitrary silica nanopatterns are fabricated on DNA origami templates by rationally designing the protruding double‐stranded DNA (dsDNA) arrays as nucleation sites. Molecular dynamic simulation confirms that the positively charged silica precursors have a stronger electrostatic affinity to protruding dsDNA than DNA origami surfaces. The site‐specific silicification of DNA nanoarchitectures expands the scope of customized synthesis of inorganic nonmetallic nanomaterials.
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