Allogeneic CD5-specific CAR-T therapy for relapsed/refractory T-ALL: a phase 1 trial.

Refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL) patients have poor prognoses, due to the lack of effective salvage therapies. Recently, CD7-targeting chimeric antigen receptor (CAR)-T therapies show efficacy in patients with r/r T-ALL, but relapse with CD7 loss is common. This study evaluates a CD5-gene-edited CAR-T cell therapy targeting CD5 in 19 r/r T-ALL patients, most of whom had previously failed CD7 CAR-T interventions. CAR-T products were derived from previous transplant donors (Cohort A) or newly matched donors (Cohort B). Primary endpoints were dose-limiting toxicity at 21 days and adverse events within 30 days. Secondary endpoints were responses, pharmacokinetics and severe adverse events after 30 days. A total of 16 received infusions, 10 at target dose of 1 × 106 kg-1. All encountered grade 3-4 cytopenias and one had a grade 3 infection within 30 days. All patients (100%) achieved complete remission or complete remission with incomplete blood count recovery by day 30. At a median follow-up of 14.3 months, four received transplantation; three were in remission and one died of infection. Of 12 untransplanted patients, 2 were in remission, 3 relapsed, 5 died of infection and 2 of thrombotic microangiopathy. CAR-T cells persisted and cleared CD5+ T cells. CD5- T cells, mostly CD5-gene-edited, increased but remained below normal levels. These results suggest this CD5-specific CAR-T intervention has a high remission rate for T-ALL patients. Evidence also suggests the risk of late-onset severe infection may be mitigated with consolidative transplantation. This study provides insights that could help to optimize this promising intervention. ClinicalTrials.gov registration: NCT05032599 .

Visible-light-driven asymmetric aldol reaction of ketones and glycinates via synergistic Lewis acid/photoredox catalysis.

Visible-light-driven direct asymmetric α-C(sp3)-H bond functionalization of glycinate provides a direct and efficient route for the synthesis of diverse optically enriched α-amino acid derivatives. However, asymmetric coupling between glycinate radical species and ketones faces significant challenges, including competitive pathways, mutable intermediates, as well as congested stereogenic centers. Herein, we disclose the first example for the asymmetric photocatalytic synthesis of a diverse array of ß-diaryl-ß-hydroxy-α-amino acetate derivatives from glycinates and heteroaryl ketones through the synergistic catalysis of achiral iridium photoredox catalyst and chiral lanthanide Lewis acid catalysts. The enantioselective radical addition pathway is supported by spectroscopic experiments, control experiments and DFT calculations.

Olig2+ single-colony-derived cranial bone-marrow mesenchymal stem cells achieve improved regeneration in a cuprizone-induced demyelination mouse model. / Olig2+å•å ‹éš†é¢ éª¨é—´å è´¨å¹²ç»†èƒžåœ¨åŒçŽ¯å·±é ®è‰é °äºŒè ™ï¼ˆCPZï¼‰è¯±å¯¼çš„å°é¼ è„±é«“éž˜æ¨¡åž‹ä¸­ä¿ƒå†ç”Ÿä½œç”¨ç ”ç©¶.

Oligodendrocytes are the myelinating cells of the central nervous system. Brain injury and neurodegenerative disease often lead to oligodendrocyte death and subsequent demyelination-related pathological changes, resulting in neurological defects and cognitive impairment (Spaas et al., 2021; Zhang J et al., 2022). Multiple sclerosis (MS) is a major demyelinating disease of the central nervous system. The pathology of MS is characterized by the loss of myelin, oligodendrocytes, and axons in the brain, brain stem, and spinal cord, as well as by white matter lesions (Lassmann et al., 2007). Unfortunately, no definitive cure for MS has been developed. Immunomodulatory and anti-inflammatory drugs are effective in the relapsing-remitting phase of MS because they reduce the frequency of relapses and the formation of inflammatory lesions; however, they do not alter the course of progressive MS and are insufficient to cure chronic neurological dysfunction (Xiao et al., 2015; Zhang et al., 2021). The treatment outcome is even worse for MS patients with primary and secondary progressions. Mesenchymal stem cells (MSCs) are stromal cells that can self-renew and exhibit multilineage differentiation. MSCs are easy to expand in vitro and exhibit low immunogenicity, no tumorigenic risks, and ethical controversies, making them a promising candidate for regenerative medicine (Zhang L et al., 2022; Xu et al., 2023). Many studies have confirmed the neural differentiation potential of MSCs under certain conditions, making them a prime candidate for treating neurodegenerative diseases (Jang et al., 2010; Yan et al., 2013). The present study investigated the effects of cranial bone-marrow mesenchymal stem cells (cBMMSCs) and oligodendrocyte-specific protein 2-positive (Olig2+) single-colony-derived cBMMSC (sc-cBMMSC), isolated in our previous work (Yang et al., 2022), in a central nervous system demyelination mouse model.

Autologous CD7 CAR-T cells generated without T cell pre-selection in pediatric patients with relapsed/refractory T-ALL: A phase I trial.

Chimeric antigen receptor (CAR)-T cell therapy showed preliminary activity in patients with refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL). However, many obstacles remain, including manufacturing difficulties and risk of infections. This phase I study (NCT04840875) evaluated autologous CD7 CAR-T cells manufactured without pre-selection of healthy T cells in r/r T-ALL. Thirty patients (29 children and one adult) with a median of two lines of prior therapy but without detectable peripheral leukemia were enrolled. Excluding three cases of manufacturing failures, a total of 27 (90%) patients received infusions after products were confirmed free of leukemia contamination, including 16 (59%) meeting planned target doses. Common adverse events within 30 days included grade 3-4 cytopenias (100%), grade 1-2 (70%) and 3-4 (7%, including one dose-limiting toxicity) cytokine release syndrome, grade 1 neurotoxicity (7%), grade 2 infection (4%), and grade 2 graft-versus-host disease (4%). Two patients developed grade 2 infections after day 30. At day 30, 96% responded and 85% achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi). Seventy-four percent underwent transplantation. Twelve-month progression-free survival with and without censoring transplantation was 22% (95% confidence interval 4%-100%) and 57% (41%-81%), respectively. These results support that autologous CD7 CAR-T therapy without T cell pre-selection is feasible in patients with r/r T-ALL.

Laser-Constructed Bionic Composite Fog-Collecting Surfaces with Efficient Nucleation Sites and Enhanced Water Transport.

Fog collection effectively alleviates the current freshwater shortage; thus, enhancing its efficiency is crucial. Here, we report a novel bionic fog collection surface (Al@B-V) comprising composite superhydrophobic bumps integrated with superhydrophilic V-channel grooves. This surface, which has efficient fog nucleation points and enhanced water transport capabilities, effectively balances fog capture and water transport during the collection process, thereby achieving high-efficiency fog collection. Compared to ordinary aluminum-based surfaces, Al@B-V achieves a fog collection efficiency of up to 3.08 g·cm-2·h-1, three times higher than the original aluminum-based surface. Furthermore, the V-channel groove proposed in this study exhibits a water transport speed of up to 165 mm·s-1, which is remarkably approximately 80 times faster than the commonly used U-channel groove. Additionally, this V-channel groove can overcome gravity, transporting approximately 10 µL of liquid to the top even when placed at 90° inclination. It can directionally transport 10 µL of liquid over a distance of up to 151 mm on a plane. This novel microgroove design can be effectively applied in various fields, including liquid collection, directional transport, seawater desalination, microfluidics, and drug delivery.

Asymmetric catalytic concise synthesis of 3-(3-indolomethyl)-oxindoles for the construction of trigolute analogs.

Asymmetric synthesis of 3-(3-indolomethyl)oxindoles through the addition of indole-substituted enolized ketoesters to 3-bromo-3-substituted oxindoles has been achieved using a N,N'-dioxide/Ho(III) complex. A number of 3-(3-indolomethyl)oxindoles, which may possess biological activity, were obtained in good yields with high diastereo- and enantioselectivities (up to 97% yield, >19 : 1 dr, 98% ee). Furthermore, time-dependent reversal of diastereoselectivity enabled access to optically active diastereomers. The product followed by facile transformations gave a new route into trigolute analogs.

Asymmetric Catalytic Synthesis of Allylic Sulfenamides from Vinyl α-Diazo Compounds by a Rearrangement Route.

The asymmetric rearrangement of allylic sulfilimines is an effective route to synthetic attractive targets such as allylic sulfenamides and others. The current methods are limited to chirality transfer from chiral allylic sulfilimine precursors. Herein, we report a general and fundamentally new rearrangement route accessing optically enriched allylic sulfenamides and their derivatives. The process involves a S-alkylation and an unusual S-to-N rearrangement step. The chiral nickel complex enables the transformation of a broad scope of sulfenamides and vinyl α-diazo pyrazoleamides under mild conditions. Various allylic sulfenamides have been synthesized with excellent γ-regioselectivity and enantioselectivity, which can be efficiently converted to sulfinamide and 4-aminobutenoic acid derivatives. In addition, DFT calculations demonstrate the connection between the spin state and conformation of nickel vinyl carbenoid, as well as an unknown rearrangement process.

Evaluation of ecosystem quality and stability based on key indicators and ideal reference frame: A case study of the Qinghai-Tibet Plateau.

China has explicitly prioritized the enhancement of ecosystem quality and stability(EQS) as a governmental objective. However, our understanding of systematic and comprehensive assessment methods for EQS remains limited. The development and investigation of corresponding evaluation frameworks and their underlying mechanisms remain insufficiently explored. This study employs the concept of an "ideal reference system and key indicators," integrating diverse ecosystem and human activity characteristics from perspectives such as ecosystem structure, function, and landscape vulnerability, to determine indicator weights using the Analytic Hierarchy Process(AHP) and entropy weight method, thereby constructing an evaluation framework for assessing the quality and stability of the Qinghai-Tibet Plateau(QTP) ecosystem. The spatiotemporal variations in EQS from 2000 to 2018 were examined, and the key driving factors were identified using the optimal parameter-based geographical detector (OPGD). The results indicate that the EQS of the QTP exhibit a spatial distribution pattern characterized by higher values in the southeast and lower values in the northwest. From 2000 to 2018, there has been a consistent improvement in the overall ecosystem quality and stability across the QTP. The EQS exhibit a significant synergistic effect, with high-high(26.59 ± 1.26%) and low-low(32.61 ± 1.45%) matching combinations becoming the predominant regional patterns. However, in climatic transition zones and glacial areas, the relationship between these factors is particularly distinctive, indicating ecosystem response mechanisms specific to certain natural environmental conditions. Vegetation cover(>0.697), evapotranspiration(>0.620), and precipitation(>0.688) are the primary natural factors influencing EQS, while the impact of human activities has become increasingly significant. Furthermore, the research findings underscore the positive effects of the variable climatic conditions of the QTP on ecosystems within the context of global climate warming, while the stringent implementation of ecological protection measures has collectively contributed to the enhancement of EQS. The proposed evaluation framework not only facilitates a comprehensive and precise assessment of regional EQS, but also provides a scientific basis for understanding and managing the adaptive responses of plateau ecosystems under the complex interplay of natural and anthropogenic factors.

Uncovering leveraging and hindering factors in socio-ecological interactions: Agricultural production in the Yellow River Basin as an example.

Agricultural production and sustainable human livelihoods in large river basins are threatened by climate change, human activities, and resource constraints. However, due to the complexity of socio-ecological interactions and agricultural sustainability, current studies are still limited by a priori knowledge and systematic analyses, as well as by the lack of quantification and identification of key factors and valuable pathway structures for agricultural production activities. Here, we combined observation-based causal inference and network analysis to quantify and assess the complex interactions in agricultural production in the Yellow River Basin (YRB) based on data from 12 factors relevant to agriculture over 40 years. We quantitatively assessed the leveraging and hindering roles of the factors in the interacting network system and provided managers with optimization priorities and possible causal pathways to achieve sustainable agriculture in the basin. For example, the fruit yield and income of rural households were identified as leveraging factors that positively affect the agricultural economy. Groundwater was seen as a hindering factor in dampening the negative impacts of the system, highlighting the importance of preventing groundwater depletion. Moreover, the findings suggest that spatially diverse causal interaction structures exist in the YRB and have shaped a variety of distinctive agricultural development modes. Our research ideas and results highlight both systemic considerations and the amplifying or dampening role of factors in interaction pathways, providing valuable quantitative insights into the management and intervention of sustainable agriculture in large river basins. Owing to replaceable and extensible network models, the methodology has the potential to be utilized in a variety of study areas and topics with complex socio-ecological interactions.

Correction: Asymmetric catalytic [1,3]- or [3,3]-sigmatropic rearrangement of 3-allyloxy-4H-chromenones and their analogues.

[This corrects the article DOI: 10.1039/D4SC02201G.].

Cross-scale coupling of ecosystem service flows and socio-ecological interactions in the Yellow River Basin.

As research on the full spectrum of ecosystem service (ES) generation and utilization within coupled human and natural systems (CHANS) has expanded, many studies have shown that the spatiotemporal dynamics of ESs are managed and influenced by human activities. However, there is insufficient research on how ESs are affected by bidirectional coupling between societal and ecological factors during spatial flow, particularly in terms of cross-scale impacts. These bidirectional influences between humans and nature are closely related to the utilization and transfer of ESs and affect the perception of spatiotemporal patterns of ESs and the formulation of management strategies. To fill this research gap, this study focuses on the Yellow River Basin (YRB), using network models to track the spatial dynamics of ES flows (ESFs) and the interactions between ecosystems and socio-economic systems within the basin on an annual scale from 2000 to 2020. The results highlight cross-scale impacts and feedback processes between local subbasins and the larger regional basin: As the supply-demand ratios of freshwater ESs, soil conservation ESs, and food ESs increase within individual subbasins of the YRB, more surplus ESs flow among subbasins. This not only alleviates spatial mismatches in ES supply and demand across the entire basin but also enhances the connectivity of the basin's ESF network. Subsequently, the cascading transfer and accumulation of ESs feedback into local socio-ecological interactions, with both socio-economic factors and the capacity for ES output within subbasins becoming increasingly reliant on external ES inflows. These results underscore the crucial role of ESFs within the CHANS of the YRB and imply the importance of cross-regional cooperation and cross-scale management strategies in optimizing ES supply-demand relationships. Furthermore, this study identifies the potential risks and challenges inherent in highly coupled systems. In conclusion, this work deepens the understanding of the spatial flow characteristics of ESs and their socio-ecological interactions; the analytical methods used in this study can also be applied to research on large river basins like the YRB, and even larger regional ecosystems.

Tandem catalytic allylic C-H amination and asymmetric [2,3]-rearrangement via bimetallic relay catalysis.

A bimetallic relay catalysis protocol for tandem allylic C-H amination and asymmetric [2,3]-sigmatropic rearrangement has been developed with the use of an achiral Pd0 catalyst and a chiral N,N'-dioxide-MgII complex in a one-pot operation. A series of anti-α-amino derivatives containing two stereogenic centers were prepared from readily available allylbenzenes and glycine pyrazolamide with good yields and high stereoselectivities. Moreover, the synthetic potential of this protocol was further demonstrated by the product transformations, and a catalytic cycle was proposed to illustrate the reaction process.

Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis.

Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound (CIB-1476) that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis. Mechanistically, CIB-1476 directly targeted pro-caspase-1 as an irreversible covalent inhibitor by binding to Cys285 and Cys397, resulting in more durable anti-inflammatory effects in the suppression of enzyme-dependent IL-1ß production and enzyme-independent nuclear factor κB activation. Chemoproteomic profiling demonstrated the engagement of CIB-1476 with caspase-1. CIB-1476 showed potent therapeutic effects by suppressing inflammasome activation in mice, which was abolished in Casp1-/- mice. These results warrant further development of CIB-1476 along with its analogues as a novel strategy for caspase-1 inhibitors.

Asymmetric dearomatization of benzyl 1-naphthyl ethers via [1,3] O-to-C rearrangement.

A catalytic asymmetric dearomatization reaction of benzyl 1-naphthyl ethers accelerated by a chiral N,N'-dioxide/Co(II) complex is disclosed. The reaction proceeds via an enantioselective [1,3] O-to-C rearrangement through a tight ion-pair pathway, providing a wide array of α-naphthalenone derivatives bearing an all-carbon quaternary center in high yields with excellent ee values.

Concise synthesis of chiral γ-butenolides via an allylation/lactonization cascade reaction.

A highly enantioselective allylation/lactonization cascade was developed, which provides a concise and efficient route to chiral γ-butenolides under mild conditions. Most of the reaction examples can be completed in 10 minutes with high selectivity.

Visible-Light-Promoted Enantioselective Acylation and Alkylation of Aldimines Enabled by 9-Fluorenone Electron-Shuttle Catalysis.

Chiral acyclic α-tertiary amino ketones are widely present in various natural products and pharmaceuticals; however, the direct synthesis of this pharmacophore through a robust strategy still presents significant challenges. The emerging photocatalysis provides a powerful approach to construct chemical bonds that are difficult to form via a traditional two-electron pathway. Herein, we developed visible-light-induced chiral Lewis acid-catalyzed highly enantioselective acylation/alkylation of aldimines enabled by cooperative FLN (9-fluorenone) electron-shuttle catalysis via radical addition. An array of α-tertiary amino ketones, ß-amino alcohols, and chiral amines were achieved with high yields and good to excellent stereocontrol (87 examples, up to 84% yield, 96% ee). These products can be easily transformed into valuable and bioactive skeletons. Extensive control experiments, detailed mechanism studies, and density functional theory calculations elucidated the reaction process and highlighted the crucial role played by FLN.

Enantioselective Synthesis of Spiro[cyclopentane-1,3'-oxindole] Scaffolds with Five Consecutive Stereocenters.

A highly diastereo- and enantioselective cascade annulation reaction of Morita-Baylis-Hillman (MBH) maleimides of isatins with ortho-hydroxychalcones was achieved by a chiral N,N'-dioxide/Mg(II) complex Lewis acid catalyst. This strategy provides a concise and efficient route to densely functionalized spiro[cyclopentane-1,3'-oxindole] compounds with five consecutive stereocenters. The reaction itself features mild conditions, good functional group compatibility, and broad substrate scope (62 examples, up to 99% yield, up to >20:1 dr, 97% ee). In addition, an obvious ligand acceleration effect and chiral amplification effect were observed. DFT calculations were performed to elucidate the stereoselectivity observed. The gram-scale synthesis and the inhibitory effect of two products on the viability of A549 cells demonstrate the potential utility of the current method.

Asymmetric catalytic [1,3]- or [3,3]-sigmatropic rearrangement of 3-allyloxy-4H-chromenones and their analogues.

A highly efficient asymmetric [1,3]- and [3,3]-O-to-C sigmatropic rearrangement of 3-allyloxy-4H-chromenones and their analogues was developed. Chiral N,N'-dioxide complexes of 3d late transition metal complexes enabled two mechanistically different processes, giving a series of optically active 2,2-disubstituted chromane-3,4-diones and 2-allyl-3-hydroxy-4H-chromen-4-ones as well as their related compounds in excellent yield and enantioselectivity. Systemic mechanistic studies and DFT calculation revealed the nature of the vinyl ether unit of the substrate, which biased regioselectivity via a stepwise tight ion pair pathway and a concerted pericyclic pathway, respectively. The enantioselectivity of the two processes is also disclosed.

Catalytic Asymmetric Dearomative [2 + 2] Photocycloaddition/Ring-Expansion Sequence of Indoles with Diversified Alkenes.

Developing novel strategies for catalytic asymmetric dearomatization (CADA) reactions is highly valuable. Visible light-mediated photocatalysis is demonstrated to be a powerful tool to activate aromatic compounds for further synthetic transformations. Herein, a catalytic asymmetric dearomative [2 + 2] photocycloaddition/ring-expansion sequence of indoles with simple alkenes was reported, providing a facile access to enantioenriched cyclopenta[b]indoles with good to high yields and enantioselectivities by means of chiral lanthanide photocatalysis. This protocol exhibited a broad substrate scope and good functional group tolerance, as well as potential applications in the synthesis of bioactive molecules. Mechanistic studies, including control experiments, UV-vis absorption spectroscopy, emission spectroscopy, and DFT calculations, were carried out, shedding insights into the reaction mechanism and the origin of enantioselectivity.

C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial.

Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1-2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.