Integrating isothermal nucleic acid amplification with CRISPR/Cas12a trans-cleavage has emerged as a powerful strategy for ultrasensitive molecular diagnostics. However, most systems depend on multiple probes, separated amplification modules, or complex probe networks, increasing design complexity, optimization burden, and instability. Herein, we report a dimeric palindromic hairpin-programmed cascade amplification strategy for synchronous dual-Cas12a activation and ultrasensitive molecular diagnostics. The distinctive feature of this design lies in the construction of a single self-dimerizing palindromic hairpin (PaH) probe integrating target recognition, primer-initiated extension, nicking-site formation, cyclic trigger generation, and palindrome-directed trigger assembly. miRNA-155 was selected as a model biomarker to initiate the single-probe amplification process. Upon target recognition, the dimeric palindromic hairpin probe undergoes Phi29 polymerase-mediated extension and Nt.BbvCI-assisted cyclic nicking, continuously generating palindromic trigger strands. These triggers undergo intermolecular hybridization and polymerase-driven elongation to produce extended duplex structures containing dual crRNA-binding sites, synchronously activating two Cas12a complexes from one cascade amplification output. Owing to this architecture-embedded cascade amplification and dual-Cas12a trans-cleavage mechanism, provided a quantitative range of 1 fM to 1 nM, with a calculated detection limit of 55 aM. The assay exhibited high sequence specificity and, in a preliminary proof-of-concept evaluation using total miRNA extracts from a small cohort of healthy individuals and breast cancer patients, generated significantly different fluorescence responses between the two groups. By integrating multiple amplification and signal-transduction functions into a single probe architecture, this work provides a compact framework for constructing high-gain CRISPR/Cas12a-based biosensing systems.

Terminal deoxynucleotidyl transferase (TdT) is a template-independent DNA polymerase that plays a critical role in immune system development and serves as an important biomarker for acute lymphoblastic leukemia. However, current methods for TdT activity analysis often rely on sophisticated instrumentation and lack simple and portable detection formats. Herein, we report a TdT-enabled multivalent CRISPR/Cas12a lateral flow assay for sensitive and instrument-free detection of TdT activity. In this strategy, TdT-catalyzed poly-adenine (poly-A) extension converts enzymatic activity into adenine-rich DNA scaffolds, which recruit multiple crRNA molecules to trigger multivalent activation of Cas12a. This design effectively bridges TdT activity with CRISPR/Cas12a signal amplification. The activated Cas12a subsequently induces trans-cleavage of a reporter probe, and the cleavage event is translated into a visual signal on a lateral flow strip. The proposed assay enables sensitive detection of TdT with a limit of detection of 0.016 U/mL and a visual detection limit of 0.05 U/mL. In addition, the assay exhibits high specificity toward TdT over other polymerases and demonstrates satisfactory performance in human serum samples with recoveries ranging from 98.8% to 103.7%. This work expands the applicability of CRISPR/Cas12a systems to enzyme activity sensing and provides a simple and practical platform for point-of-care detection of TdT.

Pulmonary fibrosis (PF) is a progressive and lethal interstitial lung disease, characterized by excessive extracellular matrix deposition and architectural distortion of the lung parenchyma. Its pathogenesis involves interconnected pathological events, including dysregulated epithelial-mesenchymal transition (EMT), chronic inflammation driven by M2-polarized macrophages, and abnormal fibroblast activation. These intertwined mechanisms contribute to the limited efficacy of current anti-fibrotic therapies, which often fail to achieve lesion-specific targeting and disease reversal. Moreover, the clinical utility of existing drugs is further hampered by poor bioavailability and insufficient accumulation at fibrotic sites. To overcome these challenges, we developed a multifunctional nanotherapeutic platform, termed HPA@NPs, through co-assembly of hyaluronic acid-platycodin D (HA-PD) and aspirin-platycodin D (ASA-PD) conjugates. This nanosystem enables concurrent modulation of multiple PF-relevant pathological features. Physicochemical characterization showed that HPA@NPs possess uniform nanoscale size, low critical aggregation concentration, and excellent colloidal stability, supporting prolonged blood circulation. In vitro, HPA@NPs showed efficient cellular uptake consistent with their HA-based design and were accompanied by inhibition of EMT, fibroblast activation, and M2 macrophage polarization, together with reduced expression of IL-10 and Arg-1. In bleomycin-induced PF mice, HPA@NPs significantly improved pulmonary function and attenuated histopathological damage. At the molecular level, HPA@NPs down-regulated fibrosis-related markers (Col1a1, TGF-β1, α-SMA), while up-regulating the epithelial tight-junction protein ZO-1 and down-regulating mesenchymal markers (N-cadherin, vimentin), confirming effective reversal of EMT. The therapeutic outcome of HPA@NPs surpassed that of monotherapy, highlighting a synergistic anti-fibrotic effect. Importantly, HPA@NPs exhibited no detectable cytotoxicity, hemolytic activity, or major organ toxicity at therapeutic doses, demonstrating favorable biocompatibility. In summary, HPA@NPs integrate precise targeting, multi-pathway synergy, and excellent biosafety, offering a promising translational strategy for PF treatment.

TP53 mutations are strongly associated with resistance to venetoclax in acute myeloid leukemia (AML) and represent a major challenge in current treatment strategies. Importantly, different TP53 mutants exhibit substantial functional heterogeneity, leading to distinct resistance phenotypes that are not adequately captured by conventional variant allele frequency (VAF)-based stratification. Emerging evidence suggests that TP53 mutations promote venetoclax resistance through multiple mechanisms, including apoptotic dysregulation, metabolic reprogramming, enhancement of leukemic stem cell properties, and epigenetic remodeling, with the relative contribution of each pathway varying among mutant types. This review systematically summarizes recent advances in the molecular mechanisms underlying TP53-mediated venetoclax resistance, with a particular focus on how mutant-specific functional differences shape therapeutic responses. Unlike previous broad reviews of TP53-mutated AML, this article specifically addresses venetoclax resistance as a clinically critical therapeutic challenge. We further discuss the limitations of current VAF-based classification systems and propose a practical framework that integrates mutant-specific resistance biology with precision therapeutic strategies.

BACKGROUND:Chronic inflammation in chronic obstructive pulmonary disease (COPD) arises from prolonged interactions among immune cells, functional cells, and inflammatory cytokines. The Qibai Pingfei Capsule (QBPF), a traditional Chinese medicine (TCM), has been utilized clinically for over two decades to treat COPD. However, robust evidence is required to validate its clinical effectiveness. Single-cell RNA sequencing (scRNA-seq) technology offers comprehensive insights into the immune-inflammatory microenvironment of COPD at the single-cell level, providing valuable strategies for integrating TCM into COPD management. PURPOSE:To clarify the mechanism of QBPF in treating COPD through scRNA-seq. METHODS:A randomized, double-blind, placebo-controlled, multicenter study performed to investigate the QBPF efficacy in COPD patients. PBMCs from these patients were subjected to scRNA-seq, and lung tissue scRNA-seq data were obtained from the public database (GEO: GSE162610). The regulatory mechanism of QBPF was confirmed using a COPD rat model. RESULTS:Acute exacerbation frequency was significantly decreased (p = 0.042), and CAT scores improved (p = 0.008) following QBPF treatment. Nevertheless, no significant changes were recorded in lung function, the 6-minute walk test (6MWT), or the mMRC scale. Within the QBPF group, the 6MWT (p < 0.01) and FEV₁/FVC% (p < 0.01) significantly improved from baseline to 3 months. ScRNA-seq confirmed immune dysfunction, especially the depleted NK cells and impaired activation. QBPF altered the expression of functional markers in NK cells of COPD patients, and animal studies confirmed that QBPF enhanced NK cell activity by modulating the expression of hepatitis A virus cellular receptor 2 (HAVCR2) and killer cell lectin-like receptor C2 (KLRC2). Additionally, scRNA-seq analysis revealed impaired immune function in COPD patients, specifically NK cell exhaustion and dysfunction. CONCLUSION:These findings demonstrated that QBPF can ameliorate and alleviate COPD symptoms, and its therapeutic effects have been linked to its potential to modulate NK cell function. This study provides some evidence that QBPF can improve NK cell activity in COPD.

BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is driven by the transdifferentiation of pulmonary fibroblasts into myofibroblasts, a pivotal step in disease progression. This study aimed to determine whether platycodin D (PD), a natural compound used in traditional Chinese medicine, can inhibit this process. The findings revealed that PD alleviates lung injury, reduces inflammation and oxidative stress, and markedly suppresses myofibroblast generation in both in vivo and in vitro models. OBJECTIVE:To clarify the potential of PD to inhibit myofibroblast generation and activation, which are pertinent for alleviating IPF, and to explore the associated targets and molecular mechanisms. METHODS:IPF models were used to assess the effects of PD on inflammation, oxidative stress, and fibroblast‑to‑myofibroblast transdifferentiation. Core targets and mechanisms were identified using a comprehensive assay, which comprised transcriptome analysis and the Lip‑SMap technology. Molecular docking, molecular dynamics simulations, cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and functional recovery experiments were performed to validate the direct targets of PD and elucidate its anti‑IPF molecular actions. RESULTS:The findings revealed that PD mitigates murine lung injury, inhibits systemic and pulmonary inflammation, reduces oxidative stress, and significantly suppresses fibroblast transdifferentiation. Integrated transcriptomics and Lip‑SMap identified that PPP2R1A is a critical target regulating the PI3K/Akt pathway, suggesting a mechanistic basis for the anti‑IPF effects of PD. Subsequent molecular docking, molecular dynamics simulations, CETSA, and SPR confirmed that PPP2R1A is a direct target of PD. Small interfering RNA knockdown and functional recovery assays demonstrated that PD binds PPP2R1A, stabilizes and activates protein phosphatase 2A (PP2A), and thereby inhibits PI3K/Akt signaling. This inhibition is likely the mechanism by which PD blocks myofibroblast transdifferentiation. CONCLUSION:PD may at least partially inhibit the PI3K/Akt signaling pathway by directly targeting PPP2R1A to stabilize and activate PP2A, thereby suppressing myofibroblast transdifferentiation and alleviating IPF.

Radiation pneumonitis (RP), a major dose-limiting toxicity of thoracic radiotherapy, is primarily driven by excessive reactive oxygen species (ROS) accumulation and proinflammatory macrophage activation, yet effective therapeutic strategies remain unavailable. Herein, we constructed Ti3CN nanosheets (Ti3CN NSs) via HF etching followed by ultrasonic exfoliation, enabling potent catalytic ROS scavenging and immunomodulatory activities. Leveraging their intrinsic antioxidative properties, Ti3CN NSs were systematically evaluated across cell, mice, and lung organoid models, demonstrating robust elimination of radiation-induced ROS and restoration of pulmonary redox homeostasis. Transcriptome sequencing combined with pathway enrichment analysis revealed that Ti3CN NSs alleviated radiation-induced macrophage ferroptosis, thereby rebalancing macrophage polarization by suppressing M1 and promoting M2 polarization. In vivo, Ti3CN NSs attenuated RP progression and facilitated structural repair of injured lung tissue. Collectively, this work proposes a nanomaterial-based strategy for the prevention and treatment of RP, and highlights the critical roles of macrophage polarization and ferroptosis in radiation-induced pulmonary inflammation.

NK92MI cells are well-defined natural killer (NK) cell lines for tumor immunotherapy. In this study, we investigated a combination therapy of MUC-1 and PD-L1 targeted chimeric antigen receptor NK92MI (CAR-NK92MI) cells for advanced non-small cell lung cancer (NSCLC). From 2016 to 2018, 7 patients with relapsed or refractory NSCLC were included in this clinical trial (ClinicalTrials.gov number, NCT02839954.Registered in 21/07/2016.). 1:1 mixed MUC-1 and PD-L1 CAR-NK92MI cells were infused, and the dosage was set at 1 × 108 to 2 × 109 CAR-NK92MI cells once. The infusion times were ranged from 3 to 37, and the median time were 22. All patients completed CAR-NK92MI cells infusion within 1 year unless intolerable toxicities appeared or disease progression (PD) occurred. All 7 patients were well-tolerated in the treatment. No cytokine release syndrome (CRS) and serious adverse events related to CAR-NK92MI treatment were observed. 3/7 patients achieved stable disease within more than 23 months. The median progression-free survival (PFS) was 12 months (2 to 60months) from the initial treatment, and the median overall survival (OS) was 19 months (3 to 60 months). Our results demonstrated that the combined MUC-1 and PD-L1 targeted CAR-NK92MI cell therapy is safe and efficient approach for relapsed and refractory NSCLC patients with metastasis. Our study was registered in ClinicalTrials.gov ( https://classic.clinicaltrials.gov/ ) (NCT02839954) in 21/07/2016.

Glioblastoma (GBM) represents the most prevalent and aggressive primary malignant neoplasm in the adult central nervous system, exhibiting marked infiltrative growth patterns, inevitable recurrence, and dismal therapeutic outcomes with current treatment modalities. While CAR-T cell immunotherapy has demonstrated remarkable success in hematological malignancies, its clinical translation for GBM has been hampered by several fundamental limitations. A key factor among these is tumor-intrinsic heterogeneity, which drives antigen escape and therapeutic resistance. Furthermore, although autologous CAR-T approaches dominate current clinical investigations, they encounter substantial barriers including manufacturing variability, scalability constraints, and practical limitations for widespread clinical deployment. In contrast, allogeneic “off-the-shelf” CAR-T therapy holds greater potential for the future applications. γδ T cells are a particularly compelling candidate for universal CAR therapy, offering several advantages including innate MHC-unrestricted target recognition obviating the need for HLA matching, polyfunctional cytotoxic mechanisms capable of addressing heterogeneous tumor populations, and intrinsic tropism for solid tumors. However, translational implementation has been constrained by their physiological rarity, ex vivo expansion difficulties, and genetic modification inefficiencies. To address these challenges, we adopted a dual-pronged targeting strategy focusing on B7-H3 and IL13Rα2 - two surface antigens demonstrating preferential overexpression across GBM subtypes while maintaining limited distribution in normal tissues. Using phage display platform and function-based nanobody screening we identified high-affinity binders against both targets. Subsequent optimization of γδ T cell expansion protocols and lentiviral transduction parameters enabled the development of a bispecific, allogeneic CAR-γδ T cell platform. Our in vitro studies revealed that dual-target CAR-γδT cells sustained proliferative capacity under GMP-compatible culture conditions, exhibited potent and specific cytotoxicity against antigen-positive glioma cells, and critically, they showed superior elimination of target-heterogeneous tumors compared to monospecific CAR-T constructs. These results establish a robust preclinical foundation for clinical translation and highlight the therapeutic potential of combinatorial antigen targeting coupled with allogeneic γδ T cell engineering to overcome the persistent challenges in GBM immunotherapy. ### Competing Interest Statement The authors have declared no competing interest. National Natural Science Foundation of China, 82303739

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA–TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA–TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA–TXNIP axis is a promising therapeutic target for improving cancer immunotherapy. Xu et al. identify the MondoA–TXNIP signalling axis as a regulator of antitumour immune surveillance in response to lactic acid in the tumour microenvironment.

The cGAS-STING signaling pathway is a crucial innate immune pathway that senses cytosolic DNA. Pharmacological activation of the cGAS-STING pathway might be a promising strategy for cancer immunotherapy. Here, we report that the cGAS-STING pathway is a new target of telatinib, an orally available vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor that has been investigated in clinical trials. In this study, we demonstrated that telatinib induced innate immune responses in a STING-dependent manner. In addition, we determined the crystal structure of STING bound to a telatinib analog, revealing the molecular interactions underlying STING activation. Moreover, we showed that telatinib-mediated STING activation contributed to the antitumor effects in tumor-bearing mouse models. In summary, our results reveal that telatinib, a previously identified VEGFR2 inhibitor, activates STING signaling, highlighting its potential in cancer immunotherapy.

Background Research on the fatty acid metabolism related gene SLC27A2 is currently mainly focused on solid tumors, and its mechanism of action in hematological tumors has not been reported.Method This study aims to explore the pathological and immune mechanisms of the fatty acid metabolism related gene SLC27A2 in hematological tumors and verify its functional role in hematological tumors through cell experiments to improve treatment decisions and clinical outcomes of hematological tumors.Result This study identified the fatty acid metabolism related gene SLC27A2 as a common differentially expressed gene between DLBCL and AML. Immune microenvironment analysis showed that SLC27A2 was significantly positively correlated with T cell CD4 + , T cell CD8 + , endothelial cells, macrophages, and NK cells in DLBCL. In AML, there is a significant negative correlation between SLC27A2 and B cells, T cell CD8 + , and macrophages. SLC27A2 participates in the immune process of hematological tumors through T cell CD8 + and macrophages. The GESA results indicate that high expression of SLC27A2 is mainly involved in the fatty acid pathway, immune pathway, and cell cycle pathway of DLBCL. The low expression of SLC27A2 is mainly involved in the immune pathway of AML. Therefore, SLC27A2 is mainly involved in the pathological mechanisms of hematological tumors through immune pathways, and cell experiments have also confirmed that SLC27A2 is involved in the regulation of DLBCL cells.Conclusion In summary, our research results comprehensively report for the first time the mechanism of action of SLC27A2 in the immune microenvironment of DLBCL and AML, and for the first time verify the cycle and apoptotic effects of the fatty acid related gene SLC27A2 in DLBCL cells through cell experiments. Research can help improve the treatment of AML and DLBCL patients.

This study focuses on the computational analysis of solubility of an anti-cancer drug namely Temozolomide in SC-CO2, utilizing a dataset consisting of pressure and temperature as input parameters and Temozolomide solubility as the output. Temperature range between 308-338 K, and pressure between 120-400 bar were taken into account for building the models. Three regression models-K Nearest Neighbors (KNN) regression, Huber regression, and Support Vector Machine (SVM) regression-were employed to predict solubility, with hyperparameter tuning accomplished using the Cuckoo Search (CS) optimization algorithm. The updated results underscored the efficacy of these models in predicting Temozolomide solubility. Notably, the SVM regression model displayed impressive performance, yielding an R-squared score of approximately 0.976, indicating a high degree of accuracy in predicting solubility. The RMSE for SVM regression was approximately 0.000152, signifying minimal prediction error, and the Mean Absolute Error (MAE) was approximately 0.000124.

The prognostic nutritional index (PNI) has been used to assess the immunonutritional status of cancer patients and can predict the prognosis of various solid cancers, and the serum alanine transaminase (ALT)/aspartate transaminase (AST) ratio (LSR) is considered a good predictor of liver injury. A retrospective cohort analysis was conducted to investigate the relationship between the prognosis of esophageal squamous cell carcinoma (ESCC) patients and LSR or PNI, as well as to combine these two indicators (LSR-PNI) for further prognostic analysis in ESCC patients undergoing radiotherapy (RT). In this study, 134 patients with esophageal cancer were retrospectively analyzed. The Chi-square test was utilized to compare count data, and univariate and multivariate Cox proportional hazards models were employed to identify independent risk and prognostic factors. Additionally, the combination of LSR and PNI (LSR-PNI) was analyzed. This study included a cohort of 134 patients, comprising 105 males with a mean age of 70.7 years and 29 females with a mean age of 76.3 years. Pathological examination categorized 41 cases as stage I–II and 93 cases as stage III–IV. The predominant treatment modality administered was intensity-modulated radiotherapy (IMRT) for esophageal cancer. Of these patients, 96 received radiation doses ≤ 54 Gy, while 38 were administered doses > 54 Gy. Radiation-induced adverse effects were observed in 67 patients, with the remaining 67 showing no such effects. Kaplan-Meier survival analysis revealed that elevated levels of the lymphocyte-to-serum ratio (LSR) and prognostic nutritional index (PNI) were significantly correlated with improved progression-free survival (PFS) and overall survival (OS). The high-LSR group demonstrated longer PFS (14.4 vs. 9.3 months, p = 0.0469) and OS (19.9 vs. 13.7 months, p = 0.0315) compared to the low-LSR group, with respective 3-year survival rates of 18.4

Development of advanced materials for drug delivery is of great importance for efficient cancer therapy. Among various materials for drug delivery, boron nitride has attracted much attention due to its unique properties for pharmaceutical applications. The efficiency of pure boron nitride nanosheets (BNNS) and modified BNNS by Ni and Pd atoms in the delivery process of the anticancer medicine 5-fluorouracil (5-FU) is studied here within the framework of density functional theory (DFT) method in different configurations. The computational method was carried out for better understanding the new drug delivery system design and release of drug. Calculation of the adsorption energy revealed that adsorption of drug via the F atom in the perpendicular configuration was more desirable than adsorption in the perpendicular state via the O atom of the drug molecule. On the other hand, Ni and Pd improved the geometry and electronic properties of the adsorption process. The Eads increased from −3.488 for pristine BNNS to −7.365 and −8.287 eV for Ni@BNNS and Pd@BNNS, respectively. The electronic band structures demonstrated the competency of the modified BNNS for adsorption of 5-FU medicine via change in the VBM, CBM, and Egap values prior and after the molecules are adsorbed onto the surface.

The association between pretreatment albumin-to-alkaline phosphatase ratio (AAPR) and clinicopathological parameters and prognosis in lung cancer is unclear. The study aimed to identify the clinical role of pretreatment AAPR among lung cancer patients. Several databases were searched for relevant studies. The primary outcome and secondary outcome were long-term survival including the overall survival (OS) and progression-free survival (PFS) and clinicopathological characteristics, respectively. The hazard ratios (HRs) and relative risks (RRs) with 95% confidence intervals (CIs) were combined. A total of 11 publications involving 10,589 participants were included in this meta-analysis. The pooled results manifested that a lower pretreatment AAPR predicted poorer OS (HR = 0.65, 95% CI 0.59–0.71, P < 0.001) and PFS (HR = 0.68, 95% CI 0.59–0.78, P < 0.001). Furthermore, subgroup analysis for the OS and PFS based on the pathological type and treatment showed similar results and pretreatment AAPR was significantly associated with worse prognosis. Besides, pretreatment AAPR was significantly associated with male (RR = 1.08, 95% CI 1.03–1.13, P < 0.001), poor differentiation (RR = 1.33, 95% CI 1.03–1.73, P = 0.029), advanced T stage (RR = 1.25, 95% CI 1.03–1.52, P = 0.026), N stage (RR = 1.34, 95% CI 1.15–1.55, P < 0.001) and TNM stage (RR = 1.14, 95% CI 1.06–1.223, P < 0.001). Therefore, pretreatment AAPR is significantly related to prognosis and tumor stage in lung cancer and patients with a lower pretreatment AAPR are more likely to experience poor survival and advanced tumor stage.

OBJECTIVE:To explore the efficacy and mechanism of osimertinib combined with bevacizumab in treating postoperative epidermal growth factor receptor (EGFR) positive stage II-IIIA lung adenocarcinoma. METHODS:In this retrospective study, one hundred and thirty patients with postoperative EGFR positive stage II-IIIA lung adenocarcinoma were divided into two groups according to different treatment methods. Patients treated with osimertinib alone were included in the single group (65 patients). Patients treated with bevacizumab on the basis of the single group were included in the joint group (65 patients). The short-term efficacy, side effects and survival results of the two groups were counted. The changes of serum vascular endothelial growth factor, serum tumor markers and life quality before and after the treatment were observed. RESULTS:The ORR (66.15%) and DCR (86.15%) in the joint group were significantly higher than those in the single group (47.69% and 70.77%) (both P<0.05). The serum levels of VEGFA, VEGFB, VEGFC, BFGF, HDGF, SDF-1, CEA, CA153, CYFRA21-1 and CA199 in the joint group were lower than those in the single group after the treatment (all P<0.05). No significant difference was shown in the incidence of adverse reactions such as rash, diarrhea, constipation, albuminuria, hypertension and interstitial pneumonia between the joint group and the single group (all P>0.05). After the treatment, the ZPS score of the joint group was lower than that of the single group, and the KPS score was higher than that of the single group (both P<0.05). There was no significant difference in the two-year median DFS and the one or two-year DFS rate between the joint group and the single group (all P>0.05). CONCLUSION:Osimertinib combined with bevacizumab in the treatment of postoperative EGFR positive stage II-IIIA lung adenocarcinoma has evident short-term efficacy and mild side effects, which is helpful in improving the disease control rate and life quality. The mechanism may be related to the regulation of serum CEA, CA153, CYFRA21-1, CA199 levels and inhibition of VEGFA, VEGFB, VEGFC, BFGF, HDGF, and SDF-1 levels.

Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are closely related to tumorigenesis and metastasis. Thioridazine (THZ) is a usual phenothiazine antipsychotic drug that can destroy CSCs. We aimed to explore whether THZ could sensitize metastatic TNBC cells, especially the CSCs, to carboplatin (CBP) treatment. Metastatic TNBC cells, 4T1 cells, and tumor-bearing mice were treated with THZ and CBP as monotherapy or combination therapy. MTT, flow cytometry, electron microscopy, immunohistochemistry and western blotting were applied to assess the cell viability, apoptosis, mitochondrial morphology and the relevant protein levels, respectively. Tumor size and lung metastasis under different treatments as well as tumorigenesis of residual tumor cells from each group were monitored. THZ combined with CBP inhibited 4T1 tumor cell proliferation and induced apoptosis by inhibiting the PI3K-AKT-mTOR pathway and activating estrogen receptor stress. THZ also showed strong activity against breast CSCs, THZ combined with CBP significantly destroyed cancer cells, inhibited lung metastasis and relieved the tumor burden; Our data demonstrated that THZ can sensitize TNBC cells to CBP treatment and this combination therapy may provide a bright strategy for TNBC treatment by targeting both cancer cells and CSCs.

The authors did not submit an updated abstract. The original abstract should be considered final. Citation Format: Tan Li, Yi Wang, Bin Li, Xueying Hu, Liu Liu, Yangyi Bao, Qiao Li, Lin Yang, Hongxia Li. Humanized CD19 CAR-T cells in the treatment of relapsed and refractory diffuse large B-cell lymphoma: A case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT150.

Cancer stem cells (CSCs) are characterized by self-renewal and unlimited proliferation, providing a basis for tumor occurrence, metastasis, and recurrence. Because CSCs are highly resistant to conventional chemotherapy and radiotherapy, various immunotherapies, particularly chimeric antigen receptor T cell (CAR-T) therapy and dendritic cell (DC)-based vaccine therapy, are currently being developed. Accordingly, in this study, we evaluated programmed cell death ligand-1 (PD-L1) expression in colorectal CSCs (CCSCs) and non-CCSCs and designed a combination immunotherapy synchronously utilizing PD-L1-CAR-T cells together with CCSC-DC vaccine-sensitized T cells for the treatment of colorectal cancer. PD-L1-CAR-T cells specifically recognized the PD-L1 molecule on CCSCs by binding to the extracellular domain of programmed cell death-1. The CCSC-DC vaccine was prepared using CCSC lysates. We found that aldehyde dehydrogenase 1 (ALDH1)-positive CCSCs were abundant in samples from patient tumor tissues and cancer cell lines. Moreover, PD-L1 was highly expressed in ALDH1-positive CCSCs compared with that in non-CCSCs. Monotherapy with PD-L1-CAR-T cells or CCSC-DC vaccine only elicited moderate tumor remission both in vitro and in vivo. However, combination therapy markedly killed cancer cells and relieved the tumor burden in mice. Our findings may provide a novel strategy for the clinical treatment of colorectal malignancy.