The anaphase-promoting complex/cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase critically involved in cell cycle regulation. However, the pathological functions of its individual subunits, particularly in hepatocellular carcinoma (HCC), remain largely unexplored. To systematically analyze the expression and prognosis of APC/C in pan-cancer, and also focus on studying the function and mechanism of APC7 in the progression of HCC. Transcriptome data were downloaded from TCGA, ICGC, and GEO databases. The analysis of differential expression genes and clinical characteristics were performed to identify the key APC gene. Moreover, immune subtype analysis was conducted to elucidate potential functions, and immune cell infiltration was assessed using the CIBERSORT algorithm. Then, gain- and loss‐of‐function studies were employed to elucidate the role of APC7 in HCC. Finally, RNA sequencing and ubiquitination assays were employed to elucidate the underlying mechanisms of APC7 in HCC. This study systematically analyzed the expression and prognosis of various subunits of the APC/C complex in pan-cancer samples, and identified APC7 as a key subunit in HCC. APC7 exhibited the most significant upregulation in HCC and was closely associated with poor prognosis in patients. Moreover, the expression profiles of APC7 is closely related to immune checkpoint genes and tumor-infiltrating immune cells. The results of multiplex immunohistochemistry showed that APC7 overexpression markedly increased the infiltration of Foxp3⁺, CD25⁺, and CD4⁺ Treg cells. Functional studies demonstrated that the knockdown of APC7 inhibited HCC cell proliferation, migration, invasion, and G1/S phase transition, whereas overexpression of APC7 promoted these malignant phenotypes in vitro and in vivo. Mechanistically, RNA sequencing and molecular studies revealed that APC7 interacts with CDH1 to mediate ubiquitin-dependent degradation of LATS1 at K860, leading to YAP/TAZ activation. Rescue experiments confirmed that LATS1 ablation reversed the tumor-suppressive effects of APC7 knockdown. Our findings identify APC7 as a key oncogenic driver in HCC, promoting tumor progression via the Hippo signaling pathway. APC7 may represent a prognostic biomarker and a potential therapeutic target in HCC. Pan-cancer analysis of APC/C identifies APC7 as the most significantly upregulated and is strongly associated with poor prognosis in patients with HCC. APC7 expression is correlated with immune checkpoint genes and tumor-infiltrating immune cells, suggesting a role in the tumor immune microenvironment. The overexpression of APC7 promotes HCC malignant progression by facilitating proliferation, migration, invasion, and cell cycle progression. APC7 interacts with CDH1 to mediate ubiquitin-dependent degradation of LATS1 at K860, leading to YAP/TAZ activation and dysregulation of the Hippo pathway.

Purpose:Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by high morbidity and limited treatment options. Current antifibrotic agents, such as pirfenidone and nintedanib (NIN), are restricted by systemic toxicity and insufficient pulmonary targeting. This study aimed to develop an inhalable human serum albumin (HSA)-based nanoparticle system co-delivering NIN and dihydroartemisinin (DHA), termed DHA/NIN@HSA, to achieve efficient lung-targeted combinational therapy against PF. Methods:DHA/NIN@HSA nanoparticles were prepared via a self-assembly strategy and characterized for morphology, particle size, and drug-loading efficiency. Pulmonary deposition and retention profiles after airway inhalation were evaluated using in vivo fluorescence imaging. The antifibrotic efficacy and safety of DHA/NIN@HSA were further assessed in a bleomycin-induced PF mouse model. Results:DHA/NIN@HSA nanoparticles exhibited uniform particle size (125 ± 5 nm) and excellent pulmonary deposition, ensuring prolonged lung retention and reduced systemic exposure. Airway administration of DHA/NIN@HSA every 48 h significantly mitigated fibrosis progression, improved survival, and restored alveolar architecture. Mechanistically, NIN inhibited fibroblast proliferation and myofibroblast differentiation, while DHA suppressed transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling and inflammatory cytokines expression. Notably, DHA showed antifibrotic efficacy comparable to NIN with superior anti-inflammatory activity, highlighting its therapeutic potential in PF. Conclusion:Airway co-delivery of DHA/NIN@HSA achieved maximal antifibrotic efficacy, precise lung targeting, and favorable safety, providing a translatable nanotherapeutic platform for combinational therapy of PF.

BACKGROUND:The mechanisms underlying immune microenvironment remodeling remain unclear for patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). This study aims to identify the key features that change following the combination therapy in patients with uHCC. METHODS:Single-cell transcriptomic profiling was conducted on uHCC samples from the control group, pre-treatment group, and post-treatment group. The Cancer Genome Atlas (TCGA) database was obtained for prognostic analysis. Enriched genes and pathways were identified, and the association and underlying mechanisms of the identified sub-cluster of cells were elucidated in relation to other cellular components. RESULTS:A total of 82,687 cells were obtained from seven patients with uHCC. In the pre-treatment group, the CancerCells_1 was associated with epithelial-mesenchymal transition, indicating a poor prognosis, as evidenced by data from 370 HCC patients in TCGA database. In the post-treatment group, a high proportion of macrophages_FOLR2 was observed corresponding to an elevated interferon response signature score and a diminished pro-angiogenic signature score. The exhaustion of CD8+ effector T cell (CD8Teff) was mitigated by downregulating the notable expression of BHLHE40 and CXCL13. Following treatment, there was an increase in liver sinusoidal endothelial cell (LSEC), while both angiogenesis and TGF-β pathway scores were reduced. Notable changes were observed in the interactions across different cells, particularly concerning the key signatures of LGALS9_HAVCR2, CSF1_CSF1R, and VEGFB_FLT1. CONCLUSION:After combined treatment, uHCC patients were characterized by macrophages_FOLR2, CD8Teff, and LSEC, indicating a remodeling of the immune microenvironment.

Accurate assessment of Human Epidermal Growth Factor Receptor 2 (HER2) amplification and Chromosome 17 (CEP17) copy number is critical for breast cancer treatment, yet diagnostically equivocal (IHC 2+) cases remain a clinical bottleneck. This study systematically benchmarks 14 feature encoders, including 12 Pathology Foundation Models (PFMs), using 2393 whole slide images across four diverse cohorts. We specifically targeted the challenging task of resolving FISH status within equivocal cases. PFM's features generally supported higher downstream predictive performance than features from ImageNet-pretrained baselines. Notably, CLAM classifiers using H-optimus-1 and UNI2-H features achieved Area Under the Curve (AUC) exceeding 0.80 in the equivocal cohorts, compared with approximately 0.60 for CLAM classifiers using ResNet-50 features. Furthermore, we validated the feasibility of predicting CEP17 polysomy directly from H&E images (AUC 0.756). These findings establish that advanced PFMs can effectively capture subtle morphological features, offering a scalable, cost-effective auxiliary tool to refine patient triage and reduce reliance on expensive confirmatory testing.

Background Hepatitis B virus (HBV ) infection poses a critical threat to public health burden worldwide. The covalently closed circular DNAs (cccDNAs) of HBV was known to form microchromosomes and interact with host epigenetic factors. The aim of the present study is to elucidate the mechanisms of ZNF638, as a transcription factor participating viral epigenetic regulations, for its role in the suppression of HBV cccDNA transcription. Methods Using chromatin immunoprecipitation and nuclear HBV cccDNA pulldown assays to determine ZNF638 binding sites. ZNF638's regulatory effects on HBV in HBV cell models are examined by FISH-IF, qRT-PCR, and ELISA assays. The effect of ZNF638 deficiency on HBV inhibition through HBV-targeting siRNA delivery was evaluated in an in vivo model of HBV transgenic mice. Results It was found that ZNF638 was able to bind the preS and S gene regions of HBV, repressing the transcription of cccDNA upon increased modification of H3K9me3 mediated by SETDB1. HUSH complex was demonstrated to involve in the epigenetic silencing of cccDNA transcription. Subcutaneous injection of ZNF638 siRNA significantly compromised the efficacy of HBV RNAi therapy in vivo. Conclusions We conclude that ZNF638 is a repressive host factor to inhibit the transcription of HBV DNAs and potently attenuate HBV infection. The binding of ZNF638 to specific regions for recruiting HUSH complex to write H3K9me3 histone marks is required for the epigenetic silencing of cccDNA transcription

The high mortality caused by severe COVID-19 poses great challenges to the public health. However, the underlying pathogenesis of severe cases remains unclear. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation in the lung tissues of virus-infected rhesus macaques coupled with down-regulated membrane-bound ACE2, which conduces to extended virus infection and severe pathological lesions. Specifically, SARS-CoV-2 infection enhances the expression of transcriptional factor aryl hydrocarbon receptor and facilitates its nucleus translocation, which causes CD147 gene transcription and its up-regulation in protein level, thereby leading to virus susceptibility of the hosts and extended virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance of lung tissues by promoting cell death of CD4 + T cells and B cells and mediating abnormal cell-cell communications, especially for M2 macrophages. Meplazumab, a humanized anti-CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance in the lung tissues of virus-infected rhesus macaque model. Importantly, we further present the cryo-EM structure of CD147-spike complex, and identify five pairs of functional residues for their interaction, which could be interrupted by Meplazumab via steric hindrance effect. Our findings provide direct evidence for CD147-SARS-CoV-2 spike interaction and uncover the pathogenesis of severe COVID-19 caused by CD147-mediated extended virus infection.

Cryo-electron microscopy (cryo-EM) has emerged as a very powerful tool for high-resolution structure determination of macromolecule complexes. However, sample preparation remains a major bottleneck in cryo-EM workflows. Most structures were resolved not in a native solution environment, but rather in the non-physiological interfaces such as the air-water interface (AWI), where the folding/unfolding energy landscape of macromolecules may be significantly altered, leading to artifact, preferential orientation, particle disassembly or even denaturation. To address this challenge, we developed a robust, sample-independent method utilizing liposome encapsulation that preserve macromolecules in a solution-like and near native environment throughout sample preparation. Using equine spleen apoferritin and the Escherichia coli ( E. coli) ribosome as model systems, we demonstrate efficient particle incorporation into liposomes and successful high-resolution structure determination. Notably, our method yields significantly reduced particle disassembly, denaturation, and preferential orientation compared to samples on holey carbon and graphene grids. We anticipate that this approach will facilitate structural studies of other challenging macromolecular complexes that are sensitive to interfacial effects. ### Competing Interest Statement The authors have declared no competing interest. National Natural Science Foundation of China, T2221001

Hepatocellular carcinoma (HCC) is a highly malignant tumor with elevated incidence and mortality rates globally. Its complex etiology and pronounced heterogeneity present significant challenges in diagnosis and treatment. Recent advancements in artificial intelligence (AI) have demonstrated transformative potential to usher a new wave of precision oncology. Pathomics, an AI-based digital pathology technique, facilitates the extraction of extensive datasets from whole-slide histopathological images, enabling quantitative analyses to improve diagnosis, treatment, and prognostic prediction for HCC. Furthermore, emerging pathological foundation models are revolutionizing traditional paradigms and providing a robust framework for the development of specialized pathomics models tailored to specific clinical tasks in HCC. Despite its promise, pathomics research in HCC remains in its infancy, with clinical implementation hindered by challenges such as data heterogeneity, model interpretability, ethical concerns, regulatory issues, and the absence of standardized industry protocols. Future initiatives should prioritize the conduction of prospective multi-center studies, the integration of multi-modal data, the enhancement of regulatory frameworks, and the establishment of industry-wide standardized guidelines and compliant platform infrastructures to accelerate the clinical adoption of pathomics for personalized HCC treatment.

Anoikis resistance in hepatocellular carcinoma (HCC) cells boosts survival and metastasis. This study aimed to establish an anoikis-related genes (ARGs)-based model for predicting HCC patients' outcomes and investigate the clinicopathological significance and function of crucial ARGs. The transcriptional expression patterns for HCC cohorts were compiled from TCGA, GEO and ICGC. Univariate and LASSO multivariate analyses were performed to screen for prognostic ARGs. Gain- and loss-of-function studies, RNA sequencing, and mass spectrometry were employed to elucidate the underlying mechanisms of ARGs in HCC. We established a five-gene ARGs risk model for HCC prognosis, with an AUC value of 0.812 for 1-year survival. Among the five genes, Rac family small GTPase 3 (RAC3) was upregulated in HCC relative to adjacent normal tissues and negatively correlated to overall survival and disease-free survival of patients with HCC. Silence of RAC3 in HCC cells resulted in an increased cell apoptosis and diminished cell proliferation and invasion. Mechanistically, we uncovered that RAC3 binding with SOX6 propelled the advancement of HCC cells through NNMT-mediated stimulation of the cAMP/MAPK/Rap1 signaling. In particular, EHop-016, a small molecule inhibitor targeting RAC3, significantly suppressed HCC progression.

Meplazumab, a humanized CD147 antibody, showed favorable safety and clinical benefits in phase 1 and phase 2/3 seamless clinical studies. Further evaluation of its therapeutic efficacy in patients with severe COVID-19 is needed. In this phase 3 add-on study, we randomized patients with severe COVID-19 in a 1:1 ratio to receive 0.2 mg/kg meplazumab or placebo via intravenous injection, and evaluated efficacy and safety within 56 days. Between February 2023 and November 2023, 108 patients with severe COVID-19 were randomized to two groups, with their baseline characteristics generally balanced. The primary endpoint, 28-day all-cause mortality was 1.96% in the meplazumab group vs 7.69% in the placebo group (P = 0.1703). Supplementary analysis using composite strategy indicated a significant reduction of 28-day all-cause mortality in meplazumab compared to placebo (3.92% vs 15.38%, P = 0.044). Meplazumab also significantly reduced the mortality in smoking subjects on day 28 (P = 0.047) compared to placebo in supplementary analysis. The secondary endpoint, 56-day all-cause mortality, was 1.96% in the meplazumab group and 11.54% in the placebo group (P = 0.048), which was 3.92% and 15.38%, respectively (P = 0.044) by supplementary analysis. Additional secondary endpoints showed potential benefits, including increased hospital discharge rates, improved clinical outcomes, and improved viral nucleotide conversion rate. Meplazumab demonstrated good safety and tolerability, with no grade ≥ 3 TEAEs observed. These promising results indicate that meplazumab reduces mortality and enhances clinical benefits in severe COVID-19 patients with a good safety profile, providing effective and specific therapeutics for severe COVID-19 (the trial was registered at ClinicalTrials.gov (NCT05679479)).

Background Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematological malignancies; however, it faces significant challenges in treating solid tumors, including limited immune infiltration into tumor tissues and immunosuppressive tumor microenvironment. Oncolytic viruses (OVs), which selectively destroy cancer cells and trigger antitumor immune responses, offer a compelling solution to these challenges. Newcastle disease virus (NDV) is a natural OV that exhibits antitumor activity with minimal side effects in clinical studies. We hypothesized that combining NDV, engineered to express a chemokine, with tetracycline-inducible CAR T cells could synergistically enhance CAR T cell therapy efficacy against solid tumors.Methods We constructed a recombinant NDV expressing human CCL19 (rNDV19) and evaluated its therapeutic efficacy alongside doxycycline-inducible CAR T cells in an orthotopic lung cancer mouse model. Tumor burden, immune cell infiltration, and mouse survival were analyzed.Results rNDV19 retained potent oncolytic activity, significantly reducing tumor cell viability while achieving stable expression of human CCL19. rNDV19 triggered significant recruitment of CAR T cells into tumors and promoted their activity. Mechanistic analysis revealed that rNDV19 and CAR T cell combination therapy remodeled the tumor microenvironment. Transcriptomic profiling highlighted activation of critical immune pathways—including leukocyte chemotaxis, T cell differentiation, cytokine production, and immune response-activating signaling in combination therapy. These findings were further corroborated by upregulated expression of T cell activation markers like IL-2, TNF-α, IFN-γ, and cytotoxic effector molecules such as granzyme A and perforin. Therapeutically, the combination synergistically extended median survival time from 22 to 36 days, outperforming monotherapies.Conclusions The combination of rNDV19 and CAR T cells represents a promising strategy for overcoming the limitations of CAR T cell therapy for solid tumors. This approach enhances immune cell infiltration and activation, potentially converting “cold” tumors into “hot” tumors to improve therapeutic outcomes and offering a robust translational framework for solid tumor immunotherapy.

The advent of hybrid pixel array detectors and fully automated data acquisition workflows has revolutionized synchrotron light sources, enabling high-throughput collection of diffraction data from biological macromolecular crystals. However, these advancements have also created an urgent need for efficient and fully automated data processing pipelines. To address this challenge, we introduce AutoPD , an open-source high-throughput meta-pipeline for automated data processing and structure determination. Developed for the biological macromolecular crystallography beamline at the High Energy Photon Source in Beijing, AutoPD is also accessible to other academic and synchrotron users. By integrating cutting-edge parallel computing strategies, AlphaFold -assisted molecular replacement, a direct-method-based dual-space-iteration approach for model building, and an adaptive decision-making strategy that dynamically selects the optimal modeling pathway based on data quality and intermediate results, AutoPD streamlines the process from raw diffraction data and sequence files to high-precision structural models. When benchmarked against 186 recently deposited X-ray diffraction datasets from the Protein Data Bank, AutoPD successfully determined structures for 92% of cases, achieving map–model correlation values of at least 0.5 between density-modified electron density maps and the generated models. These results highlight the robustness and efficiency of AutoPD in addressing the challenges of modern structural biology, setting a new standard for automated structure determination.

Clinical studies have demonstrated that recipients of allogeneic hematopoietic cell transplantation (alloHCT), particularly those undergoing HLA-haploidentical alloHCT (haploHCT), exhibit significant immune deficiencies. However, the extent to which major histocompatibility complex (MHC) disparity independently contributes to the observed lymphocyte deficiency post-alloHCT remains unclear. While MHC matching is crucial for thymic selection of T lymphocytes, it has yet to be reported whether haploHCT alters recipient thymus homeostasis compared to MHC-matched HCT and which signaling pathways are implicated in this alteration. In this study, we established mouse models of MHC-matched HCT and haploHCT without any transplant-associated complications. Our findings indicated that MHC disparity significantly disrupted thymic architecture, suppressed thymus-specific gene expression, and resulted in impaired T-cell recovery and functionality following transplantation. Single-cell transcriptomic analysis revealed abnormally enhanced interactions involving TGFB1-TGFBR3 and LRP6-CKLF between thymic lymphocytes and epithelial cells in haploHCT recipients. Furthermore, agonists targeting the TGF-β1 and LRP6 pathways were found to compromise the functional characteristics of normal thymic T cells; conversely, appropriate inhibition of these pathways restored the differentiation and maturation phenotypes of thymic T cells derived from haploHCT recipients. Our study elucidates the independent role of MHC disparity in regulating thymus homeostasis and T-cell recovery while identifying the functional involvement of the TGF-β1 and LRP6 pathways in this context. These findings provide novel insights into the mechanisms underlying immune recovery as well as potential therapeutic strategies for modulating thymic functions following haploHCT.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy characterized by high mortality rates. This article presents a discussion of the role of ZNF652 in HCC cell proliferation and apoptosis, thereby identifying a new target for HCC treatment. The expression levels of ZNF652, circRHOT1, and SLC38A6 in HCC and healthy cells were analyzed. Cell proliferation and apoptosis were subsequently validated. The binding relationships between ZNF652 and the circRHOT1 promoter and between circRHOT1 and KAT5 were validated. The recruitment of KAT5 and H3K27ac to the SLC38A6 promoter was assessed via ChIP. Combined experiments were carried out to verify the role of the circRHOT1/SLC38A6 pathway in HCC cell proliferation and apoptosis. ZNF652, circRHOT1, and SLC38A6 were upregulated in HCC cells. ZNF652 silencing inhibited HCC cell proliferation but promoted apoptosis. Mechanistically, ZNF652 increased circRHOT1 expression at the transcriptional level and recruited KAT5 to the SLC38A6 promoter to increase H3K27ac enrichment and activate SLC38A6 expression. Combined experiments revealed that overexpression of circRHOT1 or SLC38A6 could alleviate the effects of ZNF652 silencing on HCC cell proliferation and apoptosis. In conclusion, ZNF652 transcriptionally activated circRHOT1 expression, recruited KAT5 to the SLC38A6 promoter, increased H3K27ac enrichment, and activated SLC38A6 expression, thus promoting HCC cell proliferation and inhibiting apoptosis.

Mechanosensation is essential for diverse physiological processes. While many G protein-coupled receptors (GPCRs) are known to be mechanosensitive, the underlying mechanism remains largely unknown. Here, we reveal that mechanical force induces Gq activation of mGlu2, a balance modulator residing in kinocilia, but not other 7 mGlu members. Force activates mGlu2 through a conserved N-terminal force transduction motif (FTM) via a unique cis mechanism. We engineered a potent FTM-derived peptide agonist that recapitulates force-induced activation and resolved cryo-EM structures of apo-mGlu2, FTM-mGlu2, LFTM-ΨEK-mGlu2 and LFTM-ΨEK-mGlu2-Gq. The structures reveal that an atypical FTM binding to a previously uncharacterized pocket induces asymmetric 7TM domain rearrangement, enabling Gq coupling via an ICL1-TM3/6/7 interface, fundamentally distinct from the glutamate-induced Gi coupling mode of mGlu2. Compared with Gi-coupled mGlu2, the α5 helix of Gq rotated by 180°, penetrating deeper (8 Å) into a hydrophobic pocket. Disruption of the M794 7.32 -F780 6.57 -F776 6.53 hydrophobic triad core and a conformational propagation path predominantly comprising TM6-7 residues are identified as key elements mediating force induced mGlu2 activation. Further In vivo rescue experiments support that mGlu2’s mechanosensitivity is dependent on FTM and is required for vestibular function. This work establishes a paradigm for class C GPCR mechanotransduction, revealing unprecedented structural mechanisms underlying force-induced Gq coupling and offering a chemical toolset to modulate mechanical signaling of GPCR.

Sweet taste perception influences dietary choices and metabolic health. The human sweet taste receptor, a class C G-protein-coupled receptor (GPCR) heterodimer composed of TAS1R2 and TAS1R3 (refs. 1,2), senses a wide range of sweet compounds-including natural sugars, artificial sweeteners and sweet proteins-and affects metabolic regulation beyond taste. However, the lack of three-dimensional structures hinders our understanding of its precise working mechanism. Here we present cryo-electron microscopy structures of the full-length human sweet taste receptor in apo and sucralose-bound states. These structures reveal a distinct asymmetric heterodimer architecture, with sucralose binding exclusively to the Venus flytrap domain of TAS1R2. Combining mutagenesis and molecular dynamics simulations, this work delineates the sweetener-recognition modes in TAS1R2. Structural comparisons further uncover conformational changes upon ligand binding and a unique activation mechanism. These findings illuminate the signal transduction mechanisms of chemosensory receptors in the class C GPCR family and provide the molecular basis for the design of a new generation of sweeteners.

Glioblastoma (GBM) is a prevalent brain cancer with notorious aggressiveness in adults. Standard treatment for GBM includes surgery, radiation, and administration of Temozolomide (TMZ). However, the TMZ resistance during chemotherapy poses a significant challenge. In the recent study a patient-derived TMZ-resistant GBM cell line, we found that Olaparib, a PARP inhibitor, exerted a significant tumor inhibition effect. However, the required dosage appeared to be beyond current clinical applicable levels. From a transcriptome analysis screen, a drastic upregulation of nicotinamide phosphoribosyltransferase (NAMPT) was validated in tumor cells survived from Olaparib treatments. The increased level of intracellular NAD + was sufficient to increase the cell survival from Olaparib and TMZ exposure. By optimizing the dosage of Olaparib and FK866, a NAMPT inhibitor, we were able to achieve a combination regimen allowing both effective killing and growth inhibition of TMZ-resistant GBM cells, as well as the acceptance of current clinical pharmacodynamic and toxicological standard of each component agent. The combination treatment strategy was also tested in other TMZ-resistant cell lines and 3D organoids for its potential in clinical applications. In searching for potential marker molecules to indicate the effectiveness from the double inhibition of both NAMPT and PARP activities, we profiled the plasma-detectable circRNA species of cell subjected to the combination treatments, and identified the circPTTG1IP with a negatively of predictive value. Additional investigation suggested that NAMPT expression and cellular NAD + levels were regulated by circPTTG1IP, possibly involved its interaction with NAMPT targeting miRNAs.

In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.