"Percentage" and "size" of residual viable tumor in lymph node, the performance in estimating pathologic response of lymph node in non-small cell lung cancer treated with neoadjuvant chemoimmunotherapy.

There is no universally accepted method for evaluating lymph node metastasis (LNM) in non-small cell lung cancer (NSCLC) after neoadjuvant chemoimmunotherapy. Different protocols recommend evaluating the percentage of residual viable tumor (RVT%) and metastatic tumor size (MTS). Our aim was to determine the prognostic significance of RVT% and MTS, and identify the more effective parameter for pathological evaluating LNM. Two independent cohorts were collected (derivation, n=84; external validation, n=42). All patients exhibited metastatic cancer or treatment response in lymph nodes post-surgery. In the derivation cohort, we assessed the mean and largest values of MTS and RVT% in LNM, estimating their optimal cutoffs for event-free survival (EFS) using maximally selected rank statistics. Validation was subsequently conducted in the external validation cohort. The quality of prognostic factors was evaluated using the Area Under Curve (AUC). A positive association was identified between RVT% and MTS, but an absolute association could not be conclusively established. In the derivation cohort, neither the largest MTS (cutoff=6mm, p=0.28), largest RVT% (cutoff=75%, p=0.23), nor mean RVT% (cutoff=55%, p=0.06) were associated with EFS. However, mean MTS (cutoff=4.5mm) in lymph nodes was statistically associated with EFS (p=0.018), validated by the external cohort (p=0.017). The prognostic value of MTS exceeded that of ypN staging in both cohorts, as evidenced by higher AUC values. The mean value of MTS can effectively serve as a parameter for the pathological evaluation of lymph nodes, with a threshold of 4.5mm, closely linked to EFS. Its prognostic value outperforms that of ypN staging.

HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis.

Chemotherapy is an important therapuetic strategy for colorectal cancer (CRC), but chemoresistance severely affects its efficacy, and the underlying mechanism has not been fully elucidated. Increasing evidence suggests that lipid peroxidation imbalance-mediated ferroptosis is closely associated with chemoresistance. Hence, targeting ferroptosis pathways or modulating the tolerance to oxidative stress might be an effective strategy to reverse tumor chemoresistance. HtrA serine protease 1 (HTRA1) was screened out as a CRC progression- and chemoresistance-related gene. It is highly expressed in CRC cells and negatively correlated with the prognosis of CRC patients. Gain- and loss-of-function analyses demonstrated a stimulatory role of HTRA1 on the proliferation of CRC cells. The enrichment analysis of HTRA1-interacting proteins indicated the involvement of ferroptosis in the HTRA1-mediated chemoresistance. Moreover, electron microscope analysis, as well as the ROS and MDA levels in CRC cells also confirmed the effect of HTRA1 on ferroptosis. We also verified that HTRA1 could interact with SLC7A11 through its Kazal structural domain and up-regulate the expression of SLC7A11, which in turn inhibited the ferroptosis and leaded to the chemoresistance of CRC cells to 5-FU/L-OHP. Hence, we propose that HTRA1 may be a potential therapeutic target and a prognostic indicator in CRC.

Better estimation of evapotranspiration and transpiration using an improved modified Priestly-Taylor model based on a new parameter of leaf senescence in a rice field.

Evapotranspiration (ET) is at the heart of the global water, energy, and carbon cycles. As ET is difficult and expensive to measure, it is crucial to develop estimation models that can be widely applied. Currently, an improved Priestley-Taylor (PT) model considers soil moisture stress, temperature constraints, and leaf senescence; however, its parameter (fs) for simulating crop senescence is based on empirical values, making it difficult to apply to different varieties and complex external conditions and thus challenging to generalize. We improved the parameters fs in the original model based on the chlorophyll decomposition that accompanies crop senescence through easily observable SPAD values (Soil-Plant Analysis Development readings) in the field. We validated the improved model by obtaining ET of different rice varieties in 2022 and 2023 using the energy balance residual method at the Free Air Concentration Enrichment Experimental (FACE) Facility located in Yangzhou City, China. The results showed that the simulation of leaf senescence using SPAD values was feasible and could be extended to different varieties. The new model using improved leaf senescence parameter for estimating ET and transpiration (T) in three plots (2022 and 2023) exhibited slightly enhanced accuracy, particularly at the later stages of crop growth. Moreover, the higher the T/ET ratio of the cropland, the more significant the improvement. This new development enhances the ability of PT models to estimate ET and T using readily available field observations and provides some suggestions for wider application in the field for other crop species.

Impact of platinum-based chemotherapy on the tumor mutational burden and immune microenvironment in non-small cell lung cancer with postoperative recurrence.

PURPOSE: To investigate the impact of platinum-based adjuvant chemotherapy on the immunotherapeutic biomarkers of postoperative recurrent tumors in non-small cell lung cancer (NSCLC). METHODS: This study involved twenty-two cases of NSCLC, all of which underwent postoperative platinum-based chemotherapy, with matched surgical samples obtained from both their primary tumors (PTs) and recurrent tumors (RTs). Multiplex immunofluorescence was performed to assess the tumor proportion score (TPS) and immune cells (IC) on whole sections. Whole exon sequencing (WES) was conducted to investigate the tumor mutational burden (TMB) and tumor neoantigen burden (TNB). RESULTS: Compared to paired PTs, RTs exhibited higher PD-L1 expression, along with a slightly elevated density of intratumoral PD-L1+ cells (p = 0.082) and an increased tumor proportion score (mean TPS: 40.51% vs. 28.56%, p = 0.046). Regarding IC infiltration, RTs generally demonstrated significantly lower CD8+ cytotoxic T lymphocyte (CTL) density (p = 0.011) and lower CD68+ macrophage density (p = 0.005), with a loss of tertiary lymphoid structure (TLS). The comparison between RTs and PTs revealed no significant differences in TMB (p = 0.795), whereas the count of TNB in RTs was notably increased compared to PTs (p = 0.033). Prognosis analysis indicated that a higher density of CD8+ CTLs in RTs was positively correlated with improved overall survival (OS). CONCLUSIONS: In NSCLC patients with a history of postoperative platinum-based chemotherapy, the RTs demonstrated a trend towards increased PD-L1 expression and TMB/TNB, but a state of immunosuppression characterized by decreased ICs and loss of TLS, which may potentially impact the therapeutic benefits of immunotherapy.

Heterogeneity of molecular subtyping and therapy-related marker expression in primary tumors and paired lymph node metastases of small cell lung cancer.

The classification of molecular subtypes and the identification of targetable molecules have been proposed for small cell lung cancer (SCLC) patients. Our aim was to investigate whether the expression of these markers evaluated using lymph node (LN) metastases represents that of primary tumors. We enrolled 46 surgically resected SCLC patients' primary tumors and paired mediastinal LN metastases. The protein expression of subtype-defining markers (ASCL1, NEUROD1, POU2F3, and YAP1) and therapeutic markers (DLL3, MYC, PD-L1, and MHC I) was examined by immunohistochemistry and was correlated with clinicopathological parameters and prognoses. In primary and metastatic tumors, the expression of these markers was 78.3% and 87.0%, 50.0% and 63.0%, 13.0% and 6.5%, 17.4% and 15.2%, 84.8% and 87.0%, 17.4% and 6.5%, 50.0% and 34.8%, and 60.9% and 37.0%, respectively. Positive tumor PD-L1 expression was less present in LN metastases (p = 0.015), and the same was true for MHC I expression (p = 0.036). NEUROD1 and DLL3 expression levels in metastatic tumors were stronger (p < 0.001 and p = 0.002, respectively); conversely, POU2F3, MYC, PD-L1, and MHC I expression levels were weaker (p = 0.018, p = 0.019, p = 0.001, and p < 0.001, respectively). In 15 (32.6%) patients, we observed a change in the molecular subtyping pattern, and a higher number of neuroendocrine (NE)-high phenotype patients were diagnosed when using the LN specimens (91.3% vs. 84.8%). TNM stage and postoperative chemotherapy were independent prognostic factors in surgically resected SCLC patients, and no prognostic differences were found among molecular subtypes. This study highlights the discordance of subtype-specific proteins and therapeutic markers between SCLC primary tumors and LN metastases. Additionally, our findings have therapeutic and prognostic implications and warrant further clinical investigation.

Genomic discordances and heterogeneous mutational burden, PD-L1 expression and immune infiltrates of non-small cell lung cancer metastasis.

AIMS: To investigate the genomic discordances and heterogeneous mutational burden, PD-L1 expression and immune cell (IC) infiltrates of non-small cell lung cancer (NSCLC) metastasis. METHODS: Surgical samples from 41 cases of NSCLC with metastatic tumours (MTs) and paired primary tumours (PTs) were collected. PD-L1 expression and ICs were quantified using image-based immunohistochemistry profiling. Whole exome sequencing was employed to explore discrepancies in genomic characteristics, tumour mutational burden (TMB) and tumour neoantigen burden (TNB) in 28 cases. RESULTS: Non-synonymous mutations in MTs were slightly more than in PTs, with only 42.34% of mutations shared between paired PTs and MTs. The heterogeneity of TMB showed no significant difference (p=0.785) between MTs and PTs, while TNB significantly increased in MTs (p=0.013). MTs generally exhibited a higher density of PD-L1+ cells and a higher tumour proportion score with a lower density of IC infiltrates. Subgroup analysis considering clinicopathological factors revealed that the heterogeneity of immune biomarkers was closely associated with the histology of lung adenocarcinoma, metastatic sites of extrapulmonary, time intervals and treatment history. Prognosis analysis indicated that a high density of CD8+ T cells was a low-risk factor, whereas a high density of PD-L1+ cells in MTs was a high-risk factor for cancer-related death in metastatic NSCLC. CONCLUSIONS: The mutational burden, PD-L1 expression and IC infiltrates undergo changes during NSCLC metastasis, which may impact the immunotherapeutic benefits in patients with NSCLC with metastatic progression and should be monitored according to clinical scenarios.

Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies.

BACKGROUND: Chimeric antigen receptor T (CAR-T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy. METHODS: The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells. In addition, the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models. RESULTS: The CRISPR/Cas9-based knockout screening showed that the enrichment of autophagy-related genes (ATG3, BECN1, and RB1CC1) provided protection of cancer cells from CD19 CAR-T cell-mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy. Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma. Moreover, our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation. CONCLUSIONS: These findings confirm that autophagy signaling in B-cell malignancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.

Lentinan progress in inflammatory diseases and tumor diseases.

Shiitake mushrooms are a fungal food that has been recorded in Chinese medicine to nourish the blood and qi. Lentinan (lLNT) is an active substance extracted from shiitake mushrooms with powerful antioxidant, anti-inflammatory, anti-tumor functions. Inflammatory diseases and cancers are the leading causes of death worldwide, posing a serious threat to human life and health and posing enormous challenges to global health systems. There is still a lack of effective treatments for inflammatory diseases and cancer. LNT has been approved as an adjunct to chemotherapy in China and Japan. Studies have shown that LNT plays an important role in the treatment of inflammatory diseases as well as oncological diseases. Moreover, clinical experiments have confirmed that LNT combined with chemotherapy drugs has a significant effect in improving the prognosis of patients, enhancing their immune function and reducing the side effects of chemotherapy in lung cancer, colorectal cancer and gastric cancer. However, the relevant mechanism of action of the LNT signaling pathway in inflammatory diseases and cancer. Therefore, this article reviews the mechanism and clinical research of LNT in inflammatory diseases and tumor diseases in recent years.

Payments for ecosystem services programs: A global review of contributions towards sustainability.

Payments for ecosystem services programs (PESPs) are increasingly being adopted globally to enhance sustainability outcomes. There are also hundreds of studies yearly on various aspects of PESPs, but research on their contributions to sustainability of communities and the ecosystems they depend upon at the global scale are rare. Our global review explores twelve key characteristics of PESPs at three different phases (inputs - implementation - outputs and outcomes) and their relationship types of these characteristics to sustainability outcomes. To do so, we review 376 peer-review journal articles on PESPs, and test three hypotheses related to these relationships. Our findings confirm that the relationships between each of these characteristics and sustainability outcomes are bidirectional and/or multidirectional to some extent and can be positive, negative or both, depending on specific cases and research methods used to study these relationships. The findings also disclose that separating one characteristic as the primary causal factor in any relationship or outcome is not easy as relevant characteristics are linked in a complex network. Thereby, determining key characteristics of PESPs that drive relationships for the sake of sustainability is important. Through analyzing relationships between PESP characteristics, this study offers a series of suggestions to further aid the contributions of PESPs' contributions to sustainability in the future.

Molecular Classification of Endometrial Endometrioid Carcinoma With Microcystic Elongated and Fragmented Pattern.

The studies on the molecular classification of endometrioid carcinoma (EC) with microcystic, elongated, and fragmented (MELF) pattern invasion are limited. In this study, 77 cases of ECs with MELF patterns in Chinese women were collected. The molecular classification of the fifth edition of the World Health Organization was used to classify the molecular subtypes using immunohistochemistry staining (mismatch repair [MMR]-immunohistochemistry: MSH2, MSH6, MLH1, and PMS2; p53) and Sanger sequencing targeted POLE . The results showed that the prevalence of the 4 molecular subtypes in EC with MELF pattern was 6.5% (5/77) for POLE mutation, 20.8% (16/77) for MMR deficient, 11.7% (9/77) for p53-mutant, and 61.0% (47/77) for no specific molecular profile. The clinicopathological characteristics of each subtype were compared. The p53-mutant and no specific molecular profile subgroups were associated with higher International Federation of Gynecology and Obstetrics stage and International Federation of Gynecology and Obstetrics grade, deeper myometrial invasion, lymphovascular space invasion, lymph node metastasis, and absence of tumor-infiltrating lymphocytes, whereas the POLE mutation and MMR deficient subgroups were associated with lower aggressive features and prominent tumor-infiltrating lymphocytes. Progression-free survival showed that the p53-mutant and no specific molecular profile subgroups had a poorer prognosis than the POLE mutation and MMR deficient subgroups. However, lymph node metastasis was an independent factor associated with a higher risk of disease recurrence in multivariate analysis. In conclusion, ECs with MELF patterns can be divided into 4 molecular subtypes with discrepancies in aggressive clinicopathological characteristics and tumor-infiltrating lymphocytes. Molecular classification has clinical significance in a morpho-molecular approach for ECs with MELF patterns.

An efficient context-aware approach for whole-slide image classification.

Computational pathology for gigapixel whole-slide images (WSIs) at slide level is helpful in disease diagnosis and remains challenging. We propose a context-aware approach termed WSI inspection via transformer (WIT) for slide-level classification via holistically modeling dependencies among patches on WSI. WIT automatically learns feature representation of WSI by aggregating features of all image patches. We evaluate classification performance of WIT and state-of-the-art baseline method. WIT achieved an accuracy of 82.1% (95% CI, 80.7%-83.3%) in the detection of 32 cancer types on the TCGA dataset, 0.918 (0.910-0.925) in diagnosis of cancer on the CPTAC dataset, and 0.882 (0.87-0.890) in the diagnosis of prostate cancer from needle biopsy slide, outperforming the baseline by 31.6%, 5.4%, and 9.3%, respectively. WIT can pinpoint the WSI regions that are most influential for its decision. WIT represents a new paradigm for computational pathology, facilitating the development of digital pathology tools.

An orientation-free ring feature descriptor with stain-variability normalization for pathology image matching.

Comprehensively analyzing the corresponding regions in the images of serial slices stained using different methods is a common but important operation in pathological diagnosis. To help increase the efficiency of the analysis, various image registration methods are proposed to match the corresponding regions in different images, but their performance is highly influenced by the rotations, deformations, and variations of staining between the serial pathology images. In this work, we propose an orientation-free ring feature descriptor with stain-variability normalization for pathology image matching. Specifically, we normalize image staining to similar levels to minimize the impact of staining differences on pathology image matching. To overcome the rotation and deformation issues, we propose a rotation-invariance orientation-free ring feature descriptor that generates novel adaptive bins from ring features to build feature vectors. We measure the Euclidean distance of the feature vectors to evaluate keypoint similarity to achieve pathology image matching. A total of 46 pairs of clinical pathology images in hematoxylin-eosin and immunohistochemistry straining to verify the performance of our method. Experimental results indicate that our method meets the pathology image matching accuracy requirements (error ¡ 300µm), especially competent for large-angle rotation cases common in clinical practice.

Molecular subtypes, predictive markers and prognosis in small-cell lung carcinoma.

AIMS: A new molecular subtype classification was proposed for small-cell lung carcinoma (SCLC). We aimed to further validate the classification in various SCLC patient samples using immunohistochemistry (IHC) to highlight its clinical significance. METHODS: We analysed the protein expression of four subtype (achaete-scute family BHLH transcription factor 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3) and Yes1-associated transcriptional regulator (YAP1)) and two predictive markers (delta-like ligand 3 (DLL3) and MYC) using IHC in 216 specimens from 195 SCLC patients, including 21 pairs of resected biopsy tumours. Associations among molecular subtypes, clinicopathological features and prognostic implications were also explored. RESULTS: The ASCL1, NEUROD1, POU2F3, YAP1, DLL3 and MYC-positive expression rates were 70.3%, 56.9%, 14.9%, 19.0%, 75.4% and 22.6%, respectively. DLL3 expression had positive and negative associations with that of ASCL1 and POU2F3/YAP1, respectively, whereas MYC had the opposite effect. Strong associations of ASCL1 (Ρ=0.8603, p<0.0001), NEUROD1 (Ρ=0.8326, p<0.0001), POU2F3 (Ρ=0.6950, p<0.0001) and YAP1 (Ρ=0.7466, p<0.0001) expressions were detected between paired resected biopsy tumours. In addition to SCLC-A (ASCL1-dominant), SCLC-N (NEUROD1-dominant) and SCLC-P (POU2F3-dominant), unsupervised hierarchical cluster analyses identified a fourth, quadruple-negative SCLC subtype (SCLC-QN) characterised by the low expression of all four subtype-specific proteins, and 55.4% (n=108), 27.2% (n=53), 11.8% (n=23) and 5.6% (n=11) were categorised as SCLC-A, SCLC-N, SCLC-P and SCLC-QN, respectively. Significant enrichment of SCLC-P in the combined SCLC cohort was observed, and adenocarcinoma was more prevalent in SCLC-A, while large-cell neuroendocrine carcinoma was more commonly seen in SCLC-P. No survival difference was found among molecular subtypes. CONCLUSIONS: Our results provide clinical insights into the diagnostic, prognostic and predictive significance of SCLC molecular subtype classifications.

Dynamical modelling of viral infection and cooperative immune protection in COVID-19 patients.

Once challenged by the SARS-CoV-2 virus, the human host immune system triggers a dynamic process against infection. We constructed a mathematical model to describe host innate and adaptive immune response to viral challenge. Based on the dynamic properties of viral load and immune response, we classified the resulting dynamics into four modes, reflecting increasing severity of COVID-19 disease. We found the numerical product of immune system's ability to clear the virus and to kill the infected cells, namely immune efficacy, to be predictive of disease severity. We also investigated vaccine-induced protection against SARS-CoV-2 infection. Results suggested that immune efficacy based on memory T cells and neutralizing antibody titers could be used to predict population vaccine protection rates. Finally, we analyzed infection dynamics of SARS-CoV-2 variants within the construct of our mathematical model. Overall, our results provide a systematic framework for understanding the dynamics of host response upon challenge by SARS-CoV-2 infection, and this framework can be used to predict vaccine protection and perform clinical diagnosis.

Fe/Cu diatomic catalysts for electrochemical nitrate reduction to ammonia.

Electrochemical conversion of nitrate to ammonia offers an efficient approach to reducing nitrate pollutants and a potential technology for low-temperature and low-pressure ammonia synthesis. However, the process is limited by multiple competing reactions and NO3- adsorption on cathode surfaces. Here, we report a Fe/Cu diatomic catalyst on holey nitrogen-doped graphene which exhibits high catalytic activities and selectivity for ammonia production. The catalyst enables a maximum ammonia Faradaic efficiency of 92.51% (-0.3 V(RHE)) and a high NH3 yield rate of 1.08 mmol h-1 mg-1 (at - 0.5 V(RHE)). Computational and theoretical analysis reveals that a relatively strong interaction between NO3- and Fe/Cu promotes the adsorption and discharge of NO3- anions. Nitrogen-oxygen bonds are also shown to be weakened due to the existence of hetero-atomic dual sites which lowers the overall reaction barriers. The dual-site and hetero-atom strategy in this work provides a flexible design for further catalyst development and expands the electrocatalytic techniques for nitrate reduction and ammonia synthesis.

Prognostic Value of Chromatin Structure Typing in Early-Stage Non-Small Cell Lung Cancer.

(1) Background: Chromatin structure typing has been used for prognostic risk stratification among cancer survivors. This study aimed to ascertain the prognostic values of ploidy, nucleotyping, and tumor-stroma ratio (TSR) in predicting disease progression for patients with early-stage non-small cell lung cancer (NSCLC), and to explore whether patients with different nucleotyping profiles can benefit from adjuvant chemotherapy. (2) Methods: DNA ploidy, nucleotyping, and TSR were measured by chromatin structure typing analysis (Matrix Analyser, Room4, Kent, UK). Cox proportional hazard regression models were used to assess the relationships of DNA ploidy, nucleotyping, and TSR with a 5-year disease-free survival (DFS). (3) Results: among 154 early-stage NSCLC patients, 102 were non-diploid, 40 had chromatin heterogeneity, and 126 had a low stroma fraction, respectively. Univariable analysis suggested that non-diploidy was associated with a significantly lower 5-year DFS rate. After combining DNA ploidy and nucleotyping for risk stratification and adjusting for potential confounders, the DNA ploidy and nucleotyping (PN) high-risk group and PN medium-risk group had a 4- (95% CI: 1.497-8.754) and 3-fold (95% CI: 1.196-6.380) increase in the risk of disease progression or mortality within 5 years of follow-up, respectively, compared to the PN low-risk group. In PN high-risk patients, adjuvant therapy was associated with a significantly improved 5-year DFS (HR = 0.214, 95% CI: 0.048-0.957, p = 0.027). (4) Conclusions: the non-diploid DNA status and the combination of ploidy and nucleotyping can be useful prognostic indicators to predict long-term outcomes in early-stage NSCLC patients. Additionally, NSCLC patients with non-diploidy and chromatin homogenous status may benefit from adjuvant therapy.

Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma.

BACKGROUND AIMS: Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation. METHODS: We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model. RESULTS: Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype. CONCLUSIONS: Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.

The implicit preference evaluation for the ceramic tiles with different visual features: Evidence from an event-related potential study.

Background: Ceramic tiles are popular because of their various forms, and they are often used to decorate the environment. However, few studies have applied objective methods to explore the implicit preference and visual attention of people toward ceramic tile features. Using event-related potential technology can provide neurophysiological evidence for the study and applications of tiles. Materials and methods: This study explored the influence of pattern, lightness, and color system factors of ceramic tiles on the preferences of people using a combination of subjective questionnaires and event-related potential (ERP) technology. Twelve different conditions of tiles (2 × 3 × 2) were used as stimuli. EEG data were collected from 20 participants while they watched the stimuli. Subjective preference scores and average ERPs were analyzed using analysis of variance and correlation analysis. Results: (1) Pattern, lightness, and color system factors significantly affected the subjective preference scores for tiles; the unpatterned tiles, light-toned tiles, and warm-colored tiles received higher preference scores. (2) The preferences of people for different features of tiles moderated ERP amplitudes. (3) The light-toned tiles with a high preference score caused a greater N100 amplitude than the medium-toned and dark-toned tiles; and the patterned tiles and warm-colored tiles with low preference scores induced greater P200 and N200 amplitudes. Discussion: In the early stage of visual processing, light-toned tiles attracted more attention, possibly because of the positive emotional effects related to the preference. The greater P200 and N200 elicited by the patterned and neutral-colored tiles in the middle stage of visual processing indicates that patterned and neutral-colored tiles attracted more attention. This may be due to negativity bias, where more attention is allocated to negative stimuli that people strongly dislike. From the perspective of cognitive processes, the results indicate that the lightness of ceramic tiles is the factor that people first detect, and the visual processing of pattern and color system factors of ceramic tiles belong to a higher level of visual processing. This study provides a new perspective and relevant information for assessing the visual characteristics of tiles for environmental designers and marketers involved in the ceramic tiles industry.

Ensemble Effect of Ruthenium Single-Atom and Nanoparticle Catalysts for Efficient Hydrogen Evolution in Neutral Media.

Hydrogen evolution reaction (HER) plays a key role in electrochemical water splitting, which is a sustainable way for hydrogen production. The kinetics of HER is sluggish in neutral media that requires noble metal catalysts to alleviate energy consumption during the HER process. Here, we present a catalyst comprising a ruthenium single atom (Ru1) and nanoparticle (Run) loaded on the nitrogen-doped carbon substrate (Ru1-Run/CN), which exhibits excellent activity and superior durability for neutral HER. Benefiting from the synergistic effect between single atoms and nanoparticles in the Ru1-Run/CN, the catalyst exhibits a very low overpotential down to 32 mV at a current density of 10 mA cm-2 while maintaining excellent stability up to 700 h at a current density of 20 mA cm-2 during the long-term test. Computational calculations reveal that, in the Ru1-Run/CN catalyst, the existence of Ru nanoparticles affects the interactions between Ru single-atom sites and reactants and thus improves the catalytic activity of HER. This work highlights the ensemble effect of electrocatalysts for HER and could shed light on the rational design of efficient catalysts for other multistep electrochemical reactions.