Enhancing hepatocellular carcinoma management: prognostic value of integrated CCL17, CCR4, CD73, and HHLA2 expression analysis.

PURPOSE: Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC. METHODS: 873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software. RESULTS: The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE. CONCLUSION: This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.

Analysis of Th1/Th2 cytokine and clinical characteristics of patients with head and neck squamous cell carcinoma.

A retrospective analysis was conducted on 58 patients with laryngeal and hypopharyngeal tumors and 27 patients with benign vocal cord lesions to explore the role of serum cytokines in these diseases' characteristics and immunotherapy. The differences in the levels of 12 cytokines were measured. Additionally, the study examined the correlation between T helper cells (Th)1/Th2 cytokine levels and the clinical characteristics and immunotherapy efficacy of laryngeal and hypopharyngeal cancers. The results show that the balance of Th1/Th2 is biased towards Th2 in patients with laryngeal and hypopharyngeal tumors. Among these, interleukin (IL)-6 (P = 0.021) was highly expressed in laryngeal tumors, and the expression levels of IL-1ß (P = 0.008), IL-6 (P = 0.005), and IL-8 (P = 0.05) were higher in patients with poorly differentiated laryngeal tumors. The level of IL-4 (P = 0.0048) was significantly correlated with tumor location. The expression levels of IL-2 (P = 0.010), IL-4 (P = 0.028), IL-10 (P = 0.011), IL-12p70 (P = 0.034), IL-17 (P = 0.024), tumor necrosis factor (TNF)-α (P = 0.003), and interferon (IFN)-γ (P = 0.007) were related to lymph node metastasis. The level of IFN-γ (P = 0.016) was correlated with the efficacy of neoadjuvant therapy, while the level of IFN-α (P = 0.013) was significantly correlated with programmed death ligand 1 (PD-L1) expression. The Principal Component Analysis (PCA) results showed that patients with tumors, poor differentiation, and lymph node metastasis had higher levels of Th1 and Th2 cytokine separation. In conclusion, the shift in the balance of Th1 and Th2 cytokine expression indicates higher tumor invasiveness, and IFN has potential as a circulating molecular marker for immunotherapy of head and neck squamous cell carcinoma.

Metabolomics analysis of potential functional metabolites in synbiotic ice cream made with probiotic Saccharomyces cerevisiae var. boulardii CNCM I-745 and prebiotic inulin.

Probiotic lactic acid bacteria have been widely studied, but much less was focused on probiotic yeasts in food systems. In this study, probiotic Saccharomyces cerevisiae var. boulardii CNCM I-745 was employed to prepare ice cream added with and without inulin (1%, w/v). Metabolomics analysis on the effect of inulin showed 84 and 147 differentially expressed metabolites identified in the ice cream samples from day 1 and day 30 of storage (-18 °C), respectively. Various potential functional metabolites were found, including citric acid, ornithine, D-glucuronic acid, sennoside A, stachyose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, cis-aconitic acid, gamma-aminobutyric acid, L-threonine, L-glutamic acid, tryptophan, benzoic acid, and trehalose. Higher expression of these metabolites suggested their possible roles through relevant metabolic pathways in improving survivability of the probiotic yeast and functionality of ice cream. This study provides further understanding on the metabolic characteristics of probiotic yeast that potentially affect the functionality of ice cream.

Phosphorylation of caspase-8 by RSKs via organ-constrained effects controls the sensitivity to TNF-induced death.

Caspase-8 (Casp8) serves as an initiator of apoptosis or a suppressor of necroptosis in context-dependent manner. Members of the p90 RSK family can phosphorylate caspase-8 at threonine-265 (T265), which can inactivate caspase-8 for bypassing caspase-8-mediated blockade of necroptosis and can also decrease caspase-8 level by promoting its degradation. Mutating T265 in caspase-8 to alanine (A) in mice blocked TNF-induced necroptotic cecum damage but resulted in unexpectedly massive injury in the small intestine. Here, we show RSK1, RSK2, and RSK3 redundantly function in caspase-8 phosphorylation, and the duodenum is the most severely affected part of the small intestine when T265 phosphorylation of caspase-8 was prevented. Eliminating caspase-8 phosphorylation resulted in a duodenum-specific increase in basal caspase-8 protein level, which shall be responsible for the increased sensitivity to TNF-induced damage. Apoptosis of intestinal epithelial cells (IECs) was predominant in the duodenum of TNF-treated Rsk1-/-Rsk2-/-Rsk3-/- and Casp8T265A/T265A mice, though necroptosis was also observed. The heightened duodenal injury amplified systemic inflammatory responses, as evidenced by the contribution of hematopoietic cells to the sensitization of TNF-induced animal death. Further analysis revealed that hematopoietic and non-hematopoietic cells contributed differentially to cytokine production in response to the increased cell death. Collectively, RSKs emerges as a previously overlooked regulator that, via tissue/organ-constrained inactivating caspase-8 and/or downregulating caspase-8 protein level, controls the sensitivity to TNF-induced organ injury and animal death.

Degree of disorder-regulated ion transport through amorphous monolayer carbon.

Nanopore technology, re-fueled by two-dimensional (2D) materials such as graphene and MoS2, controls mass transport by allowing certain species while denying others at the nanoscale and has a wide application range in DNA sequencing, nano-power generation, and others. With their low transmembrane transport resistance and high permeability stemming from their ultrathin nature, crystalline 2D materials do not possess nanoscale holes naturally, thus requiring additional fabrication to create nanopores. Herein, we demonstrate that nanopores exist in amorphous monolayer carbon (AMC) grown at low temperatures. The size and density of nanopores can be tuned by the growth temperature, which was experimentally verified by atomic images and further corroborated by kinetic Monte Carlo simulation. Furthermore, AMC films with varied degrees of disorder (DOD) exhibit tunable transmembrane ionic conductance over two orders of magnitude when serving as nanopore membranes. This work demonstrates the DOD-tuned property in amorphous monolayer carbon and provides a new candidate for modern membrane science and technology.

A ZBP1 isoform blocks ZBP1-mediated cell death.

ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppressor of the inflammatory signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1. Cells from mice (Ripk1D325A/D325A) with cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-dependent cell death. Intriguingly, Ripk1D325A/D325A cells die spontaneously when ZBP1-S is deleted, indicating that cell death driven by ZBP1 is under the control of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against autoinflammations.

Two binuclear Ni-inserted polyoxotantalates based on {NiTa10O32} units with catalytic activity.

Two Ni-inserted polyoxotantalates, K5.5Na2H0.5[Ni(H2O)2{NiTa10O30(OH)2}]·21H2O (1) and K6Na4[Ni(en){NiTa10O32}]·22H2O (2, en = ethanediamine), were synthesized in this work. Crystallographic data analyses reveal that 1 and 2 have similar configurations. A minor difference between these two structures is that the {Ni(H2O)2} unit in 1 is replaced by {Ni(en)} unit in 2. Notably, the other Ni in 1 and 2 is located as a heteroatom at the center of the {Ta10} unit, which is reported in POTas for the first time. Moreover, 2 exhibits excellent catalytic performance in transesterification reactions in a preliminary exploration of the catalytic ability of the synthesized POTas.

A paper-based ratiometric fluorescent sensor for NH3 detection in gaseous phase: Real-time monitoring of chilled chicken freshness.

A ratiometric fluorescence sensor platform with easy-to-use and accurate is nanoengineered for NH3 quantitative detection and visual real-time monitoring of chicken freshness using smartphones. The ratiometric fluorescent probe formed by combining the zinc ion complex and carbon dots has a double-emitted fluorescence peak. The fluorescence intensity of the complex changed can be clearly observed with the increase of the concentration of ammonia solution under 365 nm wavelength excitation. In order to detect NH3 concentration in gaseous phase, a portable paper-based sensor was designed. The sensor had a good linear relationship with NH3 concentration ranging from 10.0 to 90.0 µmol/L and the LOD value was 288 nM. This fluorescent paper-based sensor was used to check the freshness of chicken breast refrigerated at 4 °C, revealed observable shifts from blue to green. The fluorescent paper-based sensor can detect NH3 concentration in real time and simplify the monitoring process of meat freshness while ensuring accuracy and stability.

CRISPRing KRAS: A Winding Road with a Bright Future in Basic and Translational Cancer Research.

Once considered "undruggable" due to the strong affinity of RAS proteins for GTP and the structural lack of a hydrophobic "pocket" for drug binding, the development of proprietary therapies for KRAS-mutant tumors has long been a challenging area of research. CRISPR technology, the most successful gene-editing tool to date, is increasingly being utilized in cancer research. Here, we provide a comprehensive review of the application of the CRISPR system in basic and translational research in KRAS-mutant cancer, summarizing recent advances in the mechanistic understanding of KRAS biology and the underlying principles of drug resistance, anti-tumor immunity, epigenetic regulatory networks, and synthetic lethality co-opted by mutant KRAS.

Imaging study on thoracic and lumbar physiological curvature in adolescent idiopathic scoliosis / 中国骨伤

OBJECTIVE@#To observe the alteration of thoracic and lumbar physiological curvature in adolescent idiopathic scoliosis(AIS) and the difference of physiological curvature between different types of scoliosis.@*METHODS@#A retrospective analysis was conducted on 305 adolescent patients taken full spine X-ray in our hospital from January 2017 to December 2021. The patients were divided into normal group and scoliosis group. The normal group was composed of 179 patients, 79 males and 100 females, aged 10 to 18 years old with an average of (12.84±2.10) years old, with cobb agle less than 10 degrees. The scoliosis group was composed of 126 patients, 33 males and 93 females, aged 10 to 18 years old with an average of (13.92±2.20) years old. The gender, age, Risser sign, thoracic kyphosis(TK) and lumbar lordosis(LL) in 2 groups were compared, and the TK and LL were also compared between different genders, different degrees of scoliosis and different segments of scoliosis.@*RESULTS@#The female ratio(P=0.001) and age (P<0.001) in scoliosis group were higher than them in normal group; the ratio of low-grade ossification was higher in normal group than in scoliosis group(P=0.038). TK was significantly smaller in scoliosis group than in normal group(P<0.001), but there was no significant difference in LL between the 2 groups(P=0.147). There were no significant difference in TK and LL between male and female. The TK was significantly bigger in mild AIS patients than in moderate AIS patients(P<0.05), but there was no significant difference in LL between mild and moderate patients(P>0.05). The TK and LL in different segments scoliosis were not found significant difference.@*CONCLUSION@#The physiological curvature of thoracic and lumbar spine is independent of gender. The thoracic physiological curvature becomes smaller in AIS patients, but lumbar curvature remains unchanged. The thoracic physiological curvature in mild AIS patients is greater than that in moderate AIS patients, but the lumbar curvature is almost unchanged between mild and moderate scoliosis and is similar with that in normal adolescent. The alteration of thoracic and lumbar physiological curvature in AIS patients may be related to relative anterior spinal overgrowth, and the specific detailed mechanism needs to be further studied.

Status risk factors and prevention and control strategies of familial aggregation of Helicobacter pylori infection / 公共卫生与预防医学

Objective To investigate the status of familial aggregation of Helicobacter pylori (Hp) infection in Jinniu District, Chengdu, and analyze its risk factors so as to provide a basis for developing prevention and control strategies of family aggregation of Hp infection. Methods A total of 172 subjects in the Second Affiliated Hospital of Chengdu Medical College · 416 Hospital of Nuclear Industry from January 2022 to January 2023 were selected as the research subjects. All subjects underwent 13C-urea breath test (13C-UBT) to diagnose whether there was Hp infection. Analyze the current situation of family aggregation of Hp infection in the region, collect general data of survey subjects, analyze the relevant factors affecting Hp family aggregation infection, and develop prevention and control strategies based on this. Results A total of 242 people from 97 households were surveyed, and the Hp family aggregation rate was 29.33%. Univariate analysis showed that there were statistically significant differences in family aggregation of Hp infection in terms of different age groups (χ2=9.719, P=0.008), marital status (χ2=8.496, P=0.014), occupations (χ2=19.462, P2=5.457, P=0.019), previous Hp test results (χ2 =4.131, P=0.042) and test results after treatment (χ2=12.000, P=0.001), with statistical significance (P<0.05). Multivariate logistic regression analysis showed that the frequency of dining out 2 days or more per week and a positive Hp test results in the past were risk factors for family aggregation of Hp infection, while the occupation of teachers/medical staff/management/technology personnel and a negative Hp results after treatment were protective factors (P<0.05). Conclusion Family aggregation of Hp infection is related to family members' occupation, frequency of dining out, previous Hp test results and Hp test results after eradication, which deserves attention in clinical practice.

Therapeutic Effect of Savolitinib in Patients with Stage Ⅲ/Ⅳ Non-small Cell Lung Cancer / 肿瘤防治研究

Objective To analyze therapeutic effect of savolitinib in patients with stage Ⅲ/Ⅳ non-small cell lung cancer (NSCLC). Methods A total of 95 patients with MET 14 exon (METex14) jumping mutation in stage Ⅲ/Ⅳ NSCLC were divided into a control group (47 cases) and an observation group (48 cases) through a random-number table method. The patients in the control group were treated with crizotinib, whereas those in the observation group were treated with savolitinib. The clinical efficacy and incidence of toxic side effects in both groups were evaluated through a chi-square test, and survival was evaluated through Kaplan-Meier survival analysis. Results Compared with control group (31.91% and 70.21%), the objective response rate and disease control rate of the observation group were 52.08% and 87.50%, respectively (P<0.05). According to Kaplan-Meier survival analysis, the overall survival and progression free survival rates in the observation group were higher than those in the control group (Log rank χ2=8.003, 4.528; P=0.005, 0.033). No statistically significant difference in the degree of toxic side effects was found between the groups (P>0.05). Conclusion Savolitinib can improve the efficacy of treatment for stage Ⅲ/Ⅳ METex14 skip mutation NSCLC patients, prolong survival, enhance the tolerance of patients to savolitinib, and facilitate the management of adverse reactions.

The accuracy of tumor size measurement and clinical T staging for resected lung cancer: Retrospective analysis of 1 880 patients / 中国胸心血管外科临床杂志

@#Objective To elucidate the correlation between radiological tumor size (RTS) and pathological tumor size (PTS), and to evaluate the accuracy of clinical T staging. Methods Data on patients who underwent complete resection between September 2018 and June 2019 were retrospectively collected. The correlation between RTS and PTS was analyzed by and we assessed the agreement between clinical and pathologic T staging. Results Finally, 1 880 patients were included. There were 778 males and 1 102 females at average age of 57±11 years. In the entire cohort, the RTS and PTS was 19.1±13.5 mm and 17.7±14.0 mm, respectively (P<0.001). The RTS and PTS showed a strong linear correlation with the Pearson’s correlation coefficient calculated as 0.897. The mean RTS was significantly larger than PTS (P<0.001) in tumors≤3 cm, but significantly smaller in tumors>4 cm. The overall concordance rate between clinical and pathological T staging was 65.6%. Clinical staging failed to detect T4 disease in 29.4% (5/17) of patients. Male patients and the presence of cavities within nodules were independent significant factors leading to inaccurate clinical T staging. Conclusions The correlation between the tumor sizes measured on thin-section computed tomography and pathologic specimens varies with the real tumor size. Methods and techniques for improving clinical T staging accuracy is in urgent need.

Traditional Chinese Medicine in Treatment of Constipation Based on 5-HT Signaling Pathway： A Review / 中国实验方剂学杂志

Chronic constipation （CC） is one of the most common functional gastrointestinal diseases. At present， the overall therapeutic effect of CC is still not satisfactory worldwide， which seriously affects the quality of life and social function of patients. The etiology and pathophysiological mechanism of constipation are still unclear. It involves comprehensive factors such as heredity， social psychology， diet， intestinal flora imbalance， intestinal motility disorder， visceral sensitivity change， pelvic floor muscle group dysfunction and enteric nervous system （ENS） disorder. Among them， the abnormal factors of the brain-gut-microbiome axis are particularly significant. The brain-gut-microbiome axis is a complex network of interactions between the intestine and the brain， integrating and coordinating the physiological functions and pathological processes of the gastrointestinal tract. Microorganisms in the intestinal lumen play an important role in it， and can communicate with the intestinal tract and the central nervous system through nerve， endocrine and immune pathways. As a key brain-gut peptide in the regulation pathway of the brain-gut-microbiome axis， 5-hydroxytryptamine （5-HT） is involved in the regulation of gastrointestinal motility， sensation and secretion. The abnormal conduction of the 5-HT signaling pathway is closely related to the occurrence and development of constipation. Traditional Chinese medicine（TCM） is a unique precious resource in China， which has good curative effects and safety. In recent years， it has received extensive attention in the treatment of constipation. TCM and active ingredients， acupuncture and massage specifically regulate 5-HT signal transmission， so that the expressions of related molecules tend to be suitable for individual disease state levels to effectively improve constipation symptoms， with unique advantages. Therefore， this study used ''constipation''， ''intestinal flora''， ''5-HT''， and ''traditional Chinese medicine'' as the keywords to search PubMed， China National Knowledge Infrastructure （CNKI） and other literature databases. The correlation between 5-HT and constipation as well as brain-gut-microbiome axis and the research progress of TCM intervention in the 5-HT signaling pathway in the treatment of constipation were reviewed in order to explore the potential therapeutic value of 5-HT system in this disease and provide references for subsequent research.

Distinctive biochemistry profiles associated with hyperuricemia between Tibetans and Hans in China.

Purpose: We sought to identify distinct risk factors for hyperuricemia in native Tibetan and immigrant Han populations in Tibet, China. Methods: Three cohorts of male participants aged between 20 and 40 years were enrolled in this study. Biochemical parameters including serum uric acid (UA), fasting plasma glucose, insulin, lactate dehydrogenase (LDH), thyroxin, blood cell count, aminotransferase, and lipid profiles were analyzed. The association of risk factors with UA levels was evaluated using a multivariable line regression model. The effect of UA level on the biochemical parameters between the Hans and Tibetans was evaluated by two-way ANOVA. Results: The prevalence of hyperuricemia (≥420 µmol/L) was 24.8% (62/250) in the Hans, similar to 23.8% (29/136) in the Tibetans. In the regression analysis, the risk factors that were significantly associated with UA in Hans did not apply to Tibetans. Tibetans had higher fasting insulin (P<0.05) and LDH (P<0.01) levels, in contrast with lower levels of triglycerides (P<0.05), total cholesterol (P<0.01), and low-density lipoprotein-cholesterol (P<0.01) than Hans in normal UA populations. Biochemistry analysis revealed lower albumin levels (P<0.001) and higher levels of all aminotransaminase and especially alkaline phosphatase (P<0.01) in Tibetans than in Hans in both populations. Compared with Hans, Tibetans had lower serum levels of urea, creatinine, and electrolytes in the normal UA population, which were further exacerbated in the high UA population. Tibetans had comparable white blood cell counts as Hans in both normal and high UA populations. In contrast, the red blood cell count and hemoglobin concentration were much lower in Tibetans than in Hans under high UA conditions. Conclusions: The distinctive biochemistry between Tibetans and Hans may underlie the different etiologies of hyperuricemia in Tibet, China.

Spatial-temporal distribution characteristics and traceability analysis of organic matter in Shahe Reservoir (Beijing, China).

Shahe Reservoir is a key node in the upstream of the North Canal, and the water quality has gradually improved after the implementation of low water operation in 2018. The organic matter(OM) in the sediment decreased from 16.66 to 14.22%.In this study, the FI index and parallel factor method were used to investigate the traceability of OM and dissolved organic matter (DOM) in the Shahe Reservoir before and during low water level operation(LWLO), and the results showed that the terrestrial source fraction of OM in sediments was mainly related to organic-rich terrestrial plant residues carried by tributaries and overflows/outfalls during the rainy season, and the FI index indicated that the organic matter (OM) in the Shahe Reservoir before and during LWLO in each DOM in the area is derived from authigenic sources of autotrophic microorganisms, algae, etc. The parallel factor method shows that more than most of the pollutants in the DOM are input from endogenous sources and a small proportion of pollutants are input from exogenous sources. Nutrients in both sediment and interstitial water increased during the LWLO, with TN and TP levels increasing by 262.38 and 204.45 mg·kg-1 in sediment, NH4+-N, PO43--P, TN and TP in interstitial water increasing by 0.98, 1.36, 2.07 and 4.33 mg·L-1, respectively. Pearson correlation analysis and principal component analysis showed that OM was significantly correlated with nutrients: OM and TN (p < 0.01) and OM and TP (p < 0.05) in the pre-LWLO; OM and TN and TP (p < 0.01) in the LWLO.The results suggested that organic matter pollution control should be mainly carried out from the perspective of endogenous input, focusing on controlling the release of nutrients in sediments.

miR-1301-3p promotes invasion and migration and EMT progression in esophageal cancer by downregulating NBL1 expression.

BACKGROUND: Esophageal cancer (ESCA) is one of the most aggressive and lethal human malignant cancers. MicroRNA-1301-3p (miR-1301-3p) plays vital roles in a majority of malignancies. The aim of this study was to investigate the role of miR-1301-3p/NBL1 axis on ESCA cell invasion, migration, epithelial-mesenchymal transition (EMT) process, as well as its association with prognosis of ESCA patients. METHODS: The expression levels of miR-1301-3p and NBL1 were predicted by bioinformatics and further verified by RT-qPCR assays. Kaplan-Meier (K-M) plotter analysis and univariate and multivariate Cox analyses were used to evaluate the relationship between miR-1301-3p and clinicopathological variables and prognosis. The role of miR-1301-3p on cell invasion, migration was detected by transwell invasion, and wound healing assays, respectively. The EMT-related proteins were detected by western blot. The target genes and the target binding sites were predicted by bioinformatics and further determined by RT-qPCR assay. RESULTS: MiR-1301-3p was remarkably upregulated in ESCA tissues and cells, and its high expression was associated with poor prognosis of ESCA. Overexpression of miR-1301-3p promoted ESCA cell invasion, migration and mediated EMT process in vitro, whereas knockdown of miR-1301-3p showed the opposite effects. Moreover, NBL1 was predicted as a target gene of miR-1301-3p. NBL1 was lowly expressed in ESCA cells and significantly decreased after upregulation of miR-1301-3p. Meanwhile, we found that low expression of NBL1 was significantly associated with poor prognosis of ESCA patients. CONCLUSION: MiR-1301-3p is a potential biomarker for predicting the prognosis of ESCA patients. It may promote ESCA invasion, migration and EMT progression by regulating NBL1 expression.

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies.