Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies.

We report on the first-in-human clinical trial using chimeric antigen receptor (CAR) T-cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies (clinicaltrials.gov NCT04136275). Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T-cells. CAR-37 T-cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4/5 patients. Tumor responses were observed in 4/5 patients, with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in two of these patients, efforts to ablate CAR-37 T-cells (which were engineered to co-express truncated EGFR) with cetuximab, were unsuccessful. Hematopoiesis was restored in these two patients following allogeneic hematopoietic stem cell transplantation. No other severe, non-hematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T-cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of IL-18, with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37-treated patients relative to both cytopenic and non-cytopenic cohorts of CAR-19-treated cohorts of patients. In conclusion, CAR-37 T-cells exhibited anti-tumor activity, with significant CAR expansion and cytokine production. CAR-37 T-cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant.

Design of Fluorinated Elastomeric Electrolyte for Solid-State Lithium Metal Batteries Operating at Low Temperature and High Voltage.

This work demonstrates the low-temperature operation of solid-state lithium metal batteries (LMBs) through the development of a fluorinated and plastic-crystal-embedded elastomeric electrolyte (F-PCEE). The F-PCEE is formed via polymerization-induced phase separation between the polymer matrix and plastic crystal phase, offering a high mechanical strain (≈300%) and ionic conductivity (≈0.23 mS cm-1) at -10 °C. Notably, strong phase separation between two phases leads to the selective distribution of lithium (Li) salts within the plastic crystal phase, enabling superior elasticity and high ionic conductivity at low temperatures. The F-PCEE in a Li/LiNi0.8Co0.1Mn0.1O2 full cell maintains 74.4% and 42.5% of discharge capacity at -10 °C and -20 °C, respectively, compared to that at 25 °C. Furthermore, the full cell exhibits 85.3% capacity retention after 150 cycles at -10 °C and a high cut-off voltage of 4.5 V, representing one of the highest cycling performances among the reported solid polymer electrolytes for low-temperature LMBs. This work attributes the prolonged cycling lifetime of F-PCEE at -10 °C to the great mechanical robustness to suppress the Li-dendrite growth and ability to form superior LiF-rich interphases. This study establishes the design strategies of elastomeric electrolytes for developing solid-state LMBs operating at low temperatures and high voltages.

The distance of insertion points from wound margins in interrupted and vertical mattress sutures influences the tensile load capacity: An in vitro experimental study.

AIM: To determine the tensile load capacity (TLC) and the tearing characteristics for interrupted and vertical mattress sutures with different insertion points from the wound margin, and the effect of the bite size when using vertical mattress sutures. MATERIALS AND METHODS: A total of 120 gingiva and lining mucosa samples obtained from pig jaws were divided into groups according to the suturing technique (interrupted and vertical mattress sutures), distance of the insertion points from the wound margin (margin, 1, 3, and 5 mm) and bite size (1, 3, and 5 mm). The TLC of the suture and the tearing characteristics were evaluated using a tensile tester device. RESULTS: The TLC was significantly higher for vertical mattress sutures than for interrupted sutures regardless of the distance of the insertion points from the wound margin (intergroup p < .001). This distance significantly influenced the TLC for vertical mattress sutures (p < .05) but not for interrupted sutures (p > .05). Testing the tearing characteristics revealed that no tissue tearing occurred in groups when the insertion points were more than 3 mm from the wound margin. CONCLUSION: The TLC is higher for vertical mattress sutures than for interrupted sutures, and it increases when the insertion points are farther from the wound margin.

Optimization of a flow cytometry test for routine monitoring of B cell maturation antigen targeted CAR in peripheral blood.

Chimeric antigen receptor (CAR) modified T cell therapies targeting BCMA have displayed impressive activity in the treatment of multiple myeloma. There are currently two FDA licensed products, ciltacabtagene autoleucel and idecabtagene vicleucel, for treating relapsed and refractory disease. Although correlative analyses performed by product manufacturers have been reported in clinical trials, there are limited options for reliable BCMA CAR T detection assays for physicians and researchers looking to explore it as a biomarker for clinical outcome. Given the known association of CAR T cell expansion kinetics with toxicity and response, being able to quantify BCMA CAR T cells routinely and accurately in the blood of patients can serve as a valuable asset. Here, we optimized an accurate and sensitive flow cytometry test using a PE-conjugated soluble BCMA protein, with a lower limit of quantitation of 0.19% of CD3+ T cells, suitable for use as a routine assay for monitoring the frequency of BCMA CAR T cells in the blood of patients receiving either ciltacabtagene autoleucel or idecabtagene vicleucel.

Unveiling the Role of Side Chain for Improving Nonvolatile Characteristics of Conjugated Polymers-Based Artificial Synapse.

Interest has grown in services that consume a significant amount of energy, such as large language models (LLMs), and research is being conducted worldwide on synaptic devices for neuromorphic hardware. However, various complex processes are problematic for the implementation of synaptic properties. Here, synaptic characteristics are implemented through a novel method, namely side chain control of conjugated polymers. The developed devices exhibit the characteristics of the biological brain, especially spike-timing-dependent plasticity (STDP), high-pass filtering, and long-term potentiation/depression (LTP/D). Moreover, the fabricated synaptic devices show enhanced nonvolatile characteristics, such as long retention time (≈102 s), high ratio of Gmax/Gmin, high linearity, and reliable cyclic endurance (≈103 pulses). This study presents a new pathway for next-generation neuromorphic computing by modulating conjugated polymers with side chain control, thereby achieving high-performance synaptic properties.

Transcriptome Profiling of a Soybean Mutant with Salt Tolerance Induced by Gamma-ray Irradiation.

Salt stress is a significant abiotic stress that reduces crop yield and quality globally. In this study, we utilized RNA sequencing (RNA-Seq) to identify differentially expressed genes (DEGs) in response to salt stress induced by gamma-ray irradiation in a salt-tolerant soybean mutant. The total RNA library samples were obtained from the salt-sensitive soybean cultivar Kwangan and the salt-tolerant mutant KA-1285. Samples were taken at three time points (0, 24, and 72 h) from two tissues (leaves and roots) under 200 mM NaCl. A total of 967,719,358 clean reads were generated using the Illumina NovaSeq 6000 platform, and 94.48% of these reads were mapped to 56,044 gene models of the soybean reference genome (Glycine_max_Wm82.a2.v1). The DEGs with expression values were compared at each time point within each tissue between the two soybeans. As a result, 296 DEGs were identified in the leaves, while 170 DEGs were identified in the roots. In the case of the leaves, eight DEGs were related to the phenylpropanoid biosynthesis pathway; however, in the roots, Glyma.03G171700 within GmSalt3, a major QTL associated with salt tolerance in soybean plants, was differentially expressed. Overall, these differences may explain the mechanisms through which mutants exhibit enhanced tolerance to salt stress, and they may provide a basic understanding of salt tolerance in soybean plants.

Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma.

Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.

Thermally Stable Ceramic-Salt Electrolytes for Li Metal Batteries Produced from Cold Sintering Using DMF/Water Mixture Solvents.

The cold sintering process (CSP) for synthesizing oxide-based electrolytes, which uses water transient solvents and uniaxial pressure, is a promising alternative to the conventional high temperature sintering process due to its low temperature (<200 °C) and short processing time (<2 h). However, the formation of amorphous secondary phases in the intergranular regions, which results in poor ionic conductivity (σ), remains a challenge. In this study, we introduced high-boiling solvents of dimethylformamide (DMF, b.p.: 153 °C) and dimethyl sulfoxide (DMSO, b.p.: 189 °C) as transient solvents to develop composite electrolytes of Li1.5Al0.5Ge1.5(PO4)3 (LAGP) with bis(trifluoromethane)sulfonimide lithium salt (LiTFSI). Our results show that composite electrolytes processed with the DMF/water mixture (CSP LAGP-LiTFSI DMF/H2O) yield a high σ of 10-4 S cm-1 at room temperature and high relative densities of >87%. Furthermore, the composite electrolytes exhibit good thermal stability; the σ maintains its initial value after heat treatment. In contrast, the composite electrolytes processed with the DMSO/water mixture and water alone show thermal degradation. The CSP LAGP-LiTFSI DMF/H2O composite electrolytes exhibit long-term stability, showing no signs of short circuiting after 350 h at 0.1 mAh cm-2 in Li symmetric cells. Our work highlights the importance of selecting appropriate transient solvents for producing efficient and stable composite electrolytes using CSP.

Phantom study of layered sensor module for photon-counting BMD detector.

In this study, we perform bone mineral density (BMD) calculation by designing a layered sensor module (LSM) that divides high- and low-energy spectra from a single shot of X-rays. Gamma-ray evaluation supports this mechanism; low-energy gamma rays are absorbed in the front detector, whereas high-energy gamma rays are absorbed in the rear detector. In this phantom study, LSM divides a single shot of X-ray into two spectra with different distributions of energy, thereby affording X-ray images with different properties, such as contrast and gray scale. The region of interest (ROI) is classified by the Prewitt operator to sort the pixels for BMD calculation or Rs value. The calculated final value is 1.2051 g/cm2 with a standard deviation (SD) of 0.3690 g/cm2, as obtained from our previous study. An improved SD results from the layered structure with two channels for signal processing, the introduction of Rs value, and the use of Prewitt filter to sort reliable data. Overall, this study displays the feasibility of LSM for BMD calculation with a small error, thereby enabling the diagnosis of osteoporosis with novel mechanism.

Straightforward Manufacturing of 3D-Printed Metallic Structures toward Customized Electrical Components.

Metalizing three-dimensional (3D)-printed polymers has been spotlighted in the field of manufacturing high-end and customized electrical components. Conventional metalization approaches that rely on the electroless plating (ELP) process typically require the use of noble metal-based catalysts or involve multistep processes, limiting their practical applications. Herein, we propose a straightforward yet effective approach to manufacture 3D-printed polymers with conductive metal layers through a thiol-mediated ELP process without involving an additional catalytic activation process. A photocurable ternary resin based on thiol-ene-acrylate monomers was precisely designed to induce excess thiol moieties on the surface of 3D-printed structures. These exposed thiol moieties served as active sites for metal ion complexion via strong metal-sulfur bonds, allowing the deposition of metal layers on the 3D-printed polymers through the ELP. Diverse metal layers, including Cu, Ag, and NiP, could be deposited onto virtually any 3D-printed structures with high uniformity and adhesion stability. To highlight the potential application of our approach, we fabricated fully functional glucose sensors through the deposition of the Cu layer on 3D-printed electrode models, and these sensors displayed excellent nonenzymatic glucose sensing performance. The proposed approach offers great insights for designing functional metallic structures and opens up new avenues for manufacturing lightweight, customized electrical components.

Genetic Clarification of Auricularia heimuer Strains Bred and Cultivated in Korea Using the ITS and IGS1 rDNA Region Sequences.

Auricularia is one of the broadly cultivated edible mushrooms in Korea. Most of the Korean Auricularia strains used for cultivation and breeding are known as A. auricula-judae. Recently, this species has been reported to belong to a species complex. Therefore, this study was carried out to genetically clarify the bred and cultivated Korean A. auricula-judae strains. The internal transcribed spacer (ITS) and IGS1 rDNA region sequences were determined from 10 A. auricula-judae strains by PCR and sequencing. Variation in the nucleotide sequence and sequence length of the two rDNA regions were found among the seven A. auricula-judae strains. A maximum-likelihood (ML) phylogenetic tree based on the ITS sequences clearly placed all the 10 Korean A. auricula-judae strains in the A. heimuer clade of the A. auricula-judae complex. A. heimuer is diverged from A. auricula-judae. An ML phylogenetic tree based on the IGS1 sequences revealed the close relationship between Korean A. heimuer strains to Chinese A. heimuer strains. But each strain could be distinguishable by the IGS1 sequence. Furthermore, progeny strains in the seven Korean strains could be differentiated from their parental strains by the IGS1 sequence based phylogenetic tree. Our results are expected to be used to complement the distinction of domestic Auricularia cultivars.

Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function.

Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we investigated whether it is possible to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism whereby cancer cells suppress T-cell function by generating a metabolically unfavorable tumor microenvironment (TME). In an in silico screen, we identified ADA and PDK1 as metabolic regulators. We then showed that overexpression (OE) of these genes enhanced the cytolysis of CD19-specific chimeric antigen receptor (CAR) T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampened this effect. ADA-OE in CAR T cells improved cancer cytolysis under high concentrations of adenosine, the ADA substrate, and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics analysis of these CAR T cells revealed alterations of global gene expression and metabolic signatures in both ADA- and PDK1-engineered CAR T cells. Functional and immunologic analyses demonstrated that ADA-OE increased proliferation and decreased exhaustion in CD19-specific and HER2-specific CAR T cells. ADA-OE improved tumor infiltration and clearance by HER2-specific CAR T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR T cells and reveal potential targets for improving CAR T-cell therapy.

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.

Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. ADA -OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA -OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by α-HER2 CAR-T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy. Synopsis: The authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in α-CD19 and α-HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE α-HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumors in vivo .

Role of Bicontinuous Structure in Elastomeric Electrolytes for High-Energy Solid-State Lithium-Metal Batteries.

Solid-state lithium (Li)-metal batteries (LMBs) are garnering attention as a next-generation battery technology that can surpass conventional Li-ion batteries in terms of energy density and operational safety under the condition that the issue of uncontrolled Li dendrite is resolved. In this study, various plastic crystal-embedded elastomer electrolytes (PCEEs) are investigated with different phase-separated structures, prepared by systematically adjusting the volume ratio of the phases, to elucidate the structure-property-electrochemical performance relationship of the PCEE in the LMBs. At an optimal volume ratio of elastomer phase to plastic-crystal phase (i.e., 1:1), bicontinuous-structured PCEE, consisting of efficient ion-conducting, plastic-crystal pathways with long-range connectivity within a crosslinked elastomer matrix, exhibits exceptionally high ionic conductivity (≈10-3 S cm-1 ) at 20 °C and excellent mechanical resilience (elongation at break ≈ 300%). A full cell featuring this optimized PCEE, a 35 µm thick Li anode, and a high loading LiNi0.83 Mn0.06 Co0.11 O2 (NMC-83) cathode delivers a high energy density of 437 Wh kganode+cathode+electrolyte -1 . The established structure-property-electrochemical performance relationship of the PCEE for solid-state LMBs is expected to inform the development of the elastomeric electrolytes for various electrochemical energy systems.

Comparison of Hepatic Metabolite Profiles between Infant and Adult Male Mice Using 1H-NMR-Based Untargeted Metabolomics.

Although age-related characteristics of hepatic metabolism are reported, those in infants are not fully understood. In the present study, we performed untargeted metabolomic profiling of the livers of infant (3-week-old) and adult (9-week-old) male ICR mice using 1H-NMR spectroscopy and compared 35 abundant hepatic metabolite concentrations between the two groups. The liver/body weight ratio did not differ between the two groups; however, serum glucose, blood urea nitrogen, total cholesterol, and triglyceride concentrations were lower in infants than in adults. Hepatic carbohydrate metabolites (glucose, maltose, and mannose) were higher, whereas amino acids (glutamine, leucine, methionine, phenylalanine, tyrosine, and valine) were lower in infant mice than in adult mice. The concentrations of ascorbate, betaine, sarcosine, and ethanolamine were higher, whereas those of taurine, inosine, and O-phosphocholine were lower in infant mice than in adult mice. The differences in liver metabolites between the two groups could be due to differences in their developmental stages and dietary sources (breast milk for infants and laboratory chow for adults). The above results provide insights into the hepatic metabolism in infants; however, the exact implications of the findings require further investigation.

Recent Advances in Nonfullerene Acceptor-Based Layer-by-Layer Organic Solar Cells Using a Solution Process.

Recently, sequential layer-by-layer (LbL) organic solar cells (OSCs) have attracted significant attention owing to their favorable p-i-n vertical phase separation, efficient charge transport/extraction, and potential for lab-to-fab large-scale production, achieving high power conversion efficiencies (PCEs) of over 18%. This review first summarizes recent studies on various approaches to obtain ideal vertical D/A phase separation in nonfullerene acceptor (NFAs)-based LbL OSCs by proper solvent selection, processing additives, protecting solvent treatment, ternary blends, etc. Additionally, the longer exciton diffusion length of NFAs compared with fullerene derivatives, which provides a new scope for further improvement in the performance of LbL OSCs, is been discussed. Large-area device/module production by LbL techniques and device stability issues, including thermal and mechanical stability, are also reviewed. Finally, the current challenges and prospects for further progress toward their eventual commercialization are discussed.

Superhydrophobic polypropylene sorbent derived from discarded face masks: A highly efficient adsorbent for oil spill sorbent.

Globally, an estimated 130 billion face masks are used and disposed of every month. Thus, recycling or upcycling discarded face masks has attracted significant attention due to economic benefits and environmental concerns. To reduce the amount of used face masks going to waste, this study features a superhydrophobic face mask prepared by simple chemical modification with environmentally preferable alkane solvents (n-hexane, n-heptane, and n-decane), that is effective as a sorbent for oil spill cleanup. All alkanes examined increased the surface roughness of the face masks and improved face mask hydrophobicity. The heptane treated face mask (at 90 °C for 1 h), can adsorbed Arabian light crude oil up to 21 times of their weight on the water surface. In addition, chloroform, toluene, gasoline, and diesel were adsorbed 18, 13, 8 and 16 times, respectively. More importantly, heptane has a high recycling efficiency as a treatment solvent and is reusable for at least 10 cycles of mask surface treatment. Consequently, this inexpensive and easily fabricated material is a promising development in waste face mask (WFM) upcycling.

Revisiting the Classical Wide-Bandgap HOMO and Random Copolymers for Indoor Artificial Light Photovoltaics.

Organic indoor photovoltaics (IPVs) are attractive energy harvesting devices for low-power consumption electronic devices and the Internet of Things (IoTs) owing to their properties such as being lightweight, semitransparent, having multicoloring capability, and flexibility. It is important to match the absorption range of photoactive materials with the emission spectra of indoor light sources that have a visible range of 400-700 nm for IPVs to provide sustainable, high-power density. To this end, benzo[1,2-b:4,5-b']dithiophene-based homopolymer (PBDTT) is synthesized as a polymer donor, which is a classical material that has a wide bandgap with a deep highest occupied molecular orbitals (HOMO) level, and a series of random copolymers by incorporating thieno[3,4-c]pyrrole-4,6,-dione (TPD) as a weak electron acceptor unit in PBDTT. The composition of the TPD unit is varied to fine tune the absorption range of the polymers; the polymer containing 70% TPD (B30T70) perfectly covers the entire range of indoor lamps such as light-emitting diodes (LEDs) and fluorescent lamp (FL). Consequently, B30T70 shows a dramatic enhancement of the power conversion efficiency (PCE) from 1-sun (PCE: 6.0%) to the indoor environment (PCE: 18.3%) when fabricating organic IPVs by blending with PC71 BM. The simple, easy molecular design guidelines are suggested to develop photoactive materials for efficient organic IPVs.

Atomistic level aqueous dissolution dynamics of NASICON-Type Li1+xAlxTi2-x(PO4)3 (LATP).

Advancing the atomistic level understanding of aqueous dissolution of multicomponent materials is essential. We combined ReaxFF and experiments to investigate the dissolution at the Li1+xAlxTi2-x(PO4)3-water interface. We demonstrate that surface dissolution is a sequentially dynamic process. The phosphate dissolution destabilizes the NASICON structure, which triggers a titanium-rich secondary phase formation.