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Tumor-associated macrophages (TAMs) exert integrated effects in all aspects of tumor progression, including tumor cell proliferation, angiogenesis, invasion, and metastasis. Recently, considerable preclinical and clinical trials have demonstrated that TAM-targeted therapy is an effective antitumor therapeutic approach, especially as a complementary strategy in combination with conventional chemotherapy, radiotherapy, or emerging immunotherapy. Here, we review all of the current clinical trials targeting TAMs worldwide up to May 2021 and highlight instances of the synergetic therapeutic efficacy of TAM-targeted combined therapeutic strategies. In total, 606 clinical trials were conducted, including 143 tested products. There has been explosive growth in macrophage-targeted therapy around the world during the past decade. Most trials were at early phase, and two-thirds used macrophage-targeting therapy as part of a combination approach. The most common combination is that of traditional chemotherapy with TAM-targeted therapy, followed by immune checkpoint inhibitors and targeted drugs. TAM-targeted therapeutic approaches are a newly emerging but rapidly developing area of anticancer therapy, especially as a combinatorial therapeutic approach. Further investigation of promising combination strategies will pave the way to more effective anticancer therapies.

Abstract Background The aim of this research is to prospectively investigate the diagnostic performance of intravoxel incoherent motion (IVIM) using the integrated slice-specific dynamic shimming (iShim) technique in staging primary esophageal squamous cell carcinoma (ESCC) and predicting presence of lymph node metastases from ESCC. Methods Sixty-three patients with ESCC were prospectively enrolled from April 2016 to April 2019. MR and IVIM using iShim technique (b = 0, 25, 50, 75, 100, 200, 400, 600, 800 s/mm2) were performed on 3.0T MRI system before operation. Primary tumour apparent diffusion coefficient (ADC) and IVIM parameters, including true diffusion coefficient (D), pseudodiffusion coefficient (D*), pseudodiffusion fraction (f) were measured by two independent radiologists. The differences in D, D*, f and ADC values of different T and N stages were assessed. Intraclass correlation coefficients (ICCs) were calculated to evaluate the interobserver agreement between two readers. The diagnostic performances of D, D*, f and ADC values in primary tumour staging and prediction of lymph node metastasis of ESCC were determined using receiver operating characteristic (ROC) curve analysis. Results The inter-observer consensus was excellent for IVIM parameters and ADC (D: ICC = 0.922; D*: ICC = 0.892; f: ICC = 0.948; ADC: ICC = 0.958). The ADC, D, D* and f values of group T1 + T2 were significantly higher than those of group T3 + T4a [ADC: (2.55 ± 0.43) ×10− 3 mm2/s vs. (2.27 ± 0.40) ×10− 3 mm2/s, t = 2.670, P = 0.010; D: (1.82 ± 0.39) ×10− 3 mm2/s vs. (1.53 ± 0.33) ×10− 3 mm2/s, t = 3.189, P = 0.002; D*: 46.45 (30.30,55.53) ×10− 3 mm2/s vs. 32.30 (18.60,40.95) ×10− 3 mm2/s, z=-2.408, P = 0.016; f: 0.45 ± 0.12 vs. 0.37 ± 0.12, t = 2.538, P = 0.014]. The ADC, D and f values of the lymph nodes-positive (N+) group were significantly lower than those of lymph nodes-negative (N0) group [ADC: (2.10 ± 0.33) ×10− 3 mm2/s vs. (2.55 ± 0.40) ×10− 3 mm2/s, t=-4.564, P

Abstract Background Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. Methods The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. Results APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. Conclusions APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.

Abstract Background Accumulating evidence suggests that cardiovascular diseases and breast cancer share a number of common risk factors, however, evidence on the association between cardiovascular health (CVH) and breast cancer is limited. The present study aimed to assess the association of CVH, defined by Life’s Essential 8 (LE8) and genetic risk with breast cancer incidence and mortality among premenopausal and postmenopausal women. Methods We used data from the UK Biobank and conducted the multivariate Cox proportional-hazards models to examine associations of LE8 score and genetic risk with breast cancer incidence and mortality. Date on LE8 score was collected between 2006 and 2010 and composed of eight components, including behavioral metrics (diet, tobacco or nicotine exposure, physical activity, and sleep health), and biological metrics (body mass index, blood lipids, blood glucose, and blood pressure). The polygenic risk score (PRS) was calculated as the sum of effect sizes of individual genetic variants multiplied by the allele dosage. Results A total of 150,566 premenopausal and postmenopausal women were included. Compared to postmenopausal women with low LE8 score, those with high LE8 score were associated with 22% lower risk of breast cancer incidence (HR: 0.78, 95% CI: 0.70–0.87) and 43% lower risk of breast cancer mortality (HR: 0.57, 95% CI: 0.36–0.90). By contrast, we did not observe the significant association among premenopausal women. Further analyses stratified by PRS categories showed that high LE8 score was associated with 28% and 71% decreased risk of breast cancer incidence (HR: 0.72, 95% CI: 0.60–0.87) and mortality (HR: 0.29, 95% CI: 0.10–0.83) compared to low LE8 score among high genetic risk groups, but no significant associations were found among low genetic risk groups. Furthermore, compared with postmenopausal women with high LE8 score and low genetic risk, those with low LE8 score and high genetic risk were associated with increased risk of breast cancer incidence (HR: 6.26, 95% CI: 4.43–8.84). Conclusions The present study suggests that better CVH is a protective factor for both breast cancer incidence and mortality among postmenopausal women. Moreover, the risk of developing breast cancer caused by high genetic susceptibility could be largely offset by better CVH.

Abstract Background To evaluate a novel intraoperative localization technique utilizing temporary pulmonary arteriovenous occlusion for enhancing the precision of sublobar resections in early‐stage NSCLC. Methods Conducted from January to November 2023, this study involved 140 patients. During the surgery, key pulmonary vessels were identified using preoperative three‐dimensional (3D) imaging and temporarily occluded with noninvasive clamps to isolate the target lung segment. Following vascular occlusion, indocyanine green (ICG) was administered intravenously to precisely delineate the resection margins. After visually confirming the marked areas, the clamps were released, and a targeted partial resection was performed on the delineated segment. Surgical data, including operation times, surgical margins, and hospitalization costs, were collected and compared with those from a historical control group of 110 patients who underwent traditional pulmonary wedge resections. Results In the study group, the median surgical margin achieved was 16 mm, which was statistically significant compared to 15 mm in the control group (p

Abstract The members of the classic B7 family regulate the immune microenvironment of several malignant tumors. However, the potential relationship between the B7 family and the breast cancer (BrCa) tumor immune microenvironment has remained elusive. In the present study, we provide a comprehensive explanation of the expression, clinical significance, mutation, and immune cell infiltration of B7 family molecules in BrCa. First, we recruited 10 patients with BrCa surgery from the Wuxi Maternal and Child Health Hospital and performed single-cell RNA sequencing (scRNA-seq) analysis to investigate the distribution of B7 family members in multiple immune cell subsets. We focused on B7-2, B7-H3, and B7-H5 molecules of the B7 family and constructed tumor microarrays by self-recruiting patients to perform multiple immunohistochemical (mIHC) analyses and study tumor expression of B7-2, B7-H3, B7-H5 and CD8+ immune cell infiltration. B7-H5 displayed a strong correlation with CD8+ immune cell infiltration. In summary, B7-H5 provides a new perspective for the identification of immunothermal subtypes of BrCa and could function as a switch to reverse BrCa from an “immunologically cold” state to an “immunologically hot” state. Graphical abstract

Abstract Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2’s repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.

Abstract Background Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy. Methods We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno‐collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in‐house samples. Additionally, novel therapeutic targets were identified based on these established immuno‐collagenic subtypes. Results Our categorization divided tumors into three subtypes: “soft & hot” (low collagen activity and high immune infiltration), “armored & cold” (high collagen activity and low immune infiltration), and “quiescent” (low collagen activity and immune infiltration). Notably, “soft & hot” tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7‐H3), an available drug target, as strongly expressed in “armored & cold” tumors, relating with poor prognosis. Conclusion This study introduces histopathology‐based universal immuno‐collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

Abstract Nasopharyngeal carcinoma (NPC) is a distinct malignancy primarily prevalent in Southern China and Southeast Asia. Circular RNAs (circRNAs), a class of non-coding RNAs, are evolutionarily conserved and exhibit remarkable stability. Their dysregulation has been observed in various cancers, including NPC. In this review, we investigate the pivotal role of circRNAs in NPC, focusing specifically on their involvement in tumor proliferation, apoptosis, metastasis, angiogenesis, stemness, metabolism, and the tumor microenvironment. We highlight the diagnostic and prognostic potential of circRNAs in NPC, emphasizing their utility as biomarkers for early detection, disease monitoring, and prediction of treatment outcomes. Additionally, we explore the therapeutic implications of circRNAs in NPC, highlighting their potential for targeted therapies.

Abstract Background Chemoresistance and immunosuppression are two major obstacles in the current anti-cancer treatments. This study investigates the involvements of a CCAAT enhancer binding protein delta (CEBPD)/vesicle associated membrane protein 3 (VAMP3) axis in paclitaxel (PTX) resistance and immune evasion in triple-negative breast cancer (TNBC). Methods PTX resistance-related genes were screened by bioinformatics. CEBPD and VAMP3 expression in clinical TNBC samples was examined by immunohistochemistry. Three PTX-resistant TNBC cell lines (MDA-MB-231/PTX, MDA-MB-468/PTX and MDA-MB-453/PTX) were generated, and their drug resistance was analyzed. Autophagy of cells was analyzed by immunofluorescence staining. Interaction between CEBPD and VAMP3 promoter was identified by immunoprecipitation and luciferase assays. The extracellular expression of programmed cell death-ligand 1 (PD-L1) in TNBC cells was detected. Extracellular vesicles (EVs) from TNBC cells were isolated to examine their effects on CD8+ T cell exhaustion. Results CEBPD and VAMP3 were upregulated in chemo-resistant tissue samples and in PTX-resistant TNBC cells. The CEBPD downregulation enhanced PTX sensitivity of cells. However, further upregulation of VAMP3 in cells restored PTX resistance, which was likely due to the activation of autophagy, as the autophagy antagonist chloroquine enhanced PTX sensitivity of cells. CEBPD was found to bind to the VAMP3 promoter to activate its transcription. The CEBPD/VAMP3 axis also increased the PD-L1 expression in the conditioned medium of TNBC cells. The TNBC cell-derived EVs increased the exhaustion of co-cultured CD8+ T cells. Conclusion This study provides novel evidence that CEBPD plays a key role in enhancing PTX resistance in TNBC cells across various subtypes through VAMP3-mediated autophagy activation. Additionally, the CEBPD/VAMP3 axis also increases extracellular PD-L1 level, delivered by cancer cell-derived EVs, to suppress CD8+ T cell-mediated anti-tumor immune response. These significant observations may provide new insights into the treatment of TNBC, suggesting CEBPD and VAMP3 as promising targets to overcome treatment resistance.

Background: Colon cancer is one of the most prevalent digestive cancers worldwide. Results of epidemiological, experimental, and clinical studies suggest that aspirin inhibits the development of colon cancer. This study aimed to systematically elucidate the molecular mechanisms by which aspirin prevents colon carcinogenesis. Methods: We determined the global protein expression profiles of colorectal cancer and aspirin-treated cells using quantitative proteomic analysis. We analyzed the proteomic results using bioinformatics (including differential proteins, protein annotation, Kyoto Encyclopedia of Genes and Genomes [KEGG] pathways, and protein–protein interaction [PPI] network). The viability of the colon cancer cell line and HT29 ​cells treated with aspirin was determined using the cell counting kit-8 assay. The differentially expressed proteins, such as p53 and cyclin-dependent kinase 1 (CDK1), were quantified using real-time polymerase chain reaction (PCR) and Western blotting. We measured cell cycle distribution and apoptosis in HT29 ​cells exposed to aspirin using fluorescence-activated cell sorting (FACS). Results: We found that 552 proteins were significantly dysregulated, of which 208 and 334 were upregulated and downregulated, respectively, in colon cancer cells exposed to 10 ​mmol/L of aspirin (95% confidence interval [CI]: -1.269 to -0.106, P ​

Background Immune checkpoint blockade (ICB) has made remarkable achievements, but newly identified armored and cold tumors cannot respond to ICB therapy. The high prevalence of concomitant medications has huge impact on immunotherapeutic responses, but the clinical effects on the therapeutic outcome of armored and cold tumors are still unclear.Methods In this research, using large-scale transcriptomics datasets, the expression and potential biological functions of angiotensin II receptor 1 (AGTR1), the target of angiotensin receptor blocker (ARB), were investigated. Next, the roles of ARB in tumor cells and tumor microenvironment cells were defined by a series of in vitro and in vivo assays. In addition, the clinical impacts of ARB on ICB therapy were assessed by multicenter cohorts and meta-analysis.Results AGTR1 was overexpressed in armored and cold tumors and associated with poor response to ICB therapy. ARB, the inhibitor for AGTR1, only suppressed the aggressiveness of tumor cells with high AGTR1 expression, which accounted for a very small proportion. Further analysis revealed that AGTR1 was always highly expressed in cancer-associated fibroblasts (CAFs) and ARB inhibited type I collagen expression in CAFs by suppressing the RhoA-YAP axis. Moreover, ARB could also drastically reverse the phenotype of armored and cold to soft and hot in vivo, leading to a higher response to ICB therapy. In addition, both our in-house cohorts and meta-analysis further supported the idea that ARB can significantly enhance ICB efficacy.Conclusion Overall, we identify AGTR1 as a novel target in armored and cold tumors and demonstrate the improved therapeutic efficacy of ICB in combination with ARB. These findings could provide novel clinical insight into how to treat patients with refractory armored and cold tumors.

BackgroundIncreasing evidence reveals the involvement of mitochondria and macrophage polarisation in tumourigenesis and progression. This study aimed to establish mitochondria and macrophage polarisation-associated molecular signatures to predict prognosis in gastric cancer (GC) by single-cell and transcriptional data.MethodsInitially, candidate genes associated with mitochondria and macrophage polarisation were identified by differential expression analysis and weighted gene co-expression network analysis. Subsequently, candidate genes were incorporated in univariateCox analysis and LASSO to acquire prognostic genes in GC, and risk model was created. Furthermore, independent prognostic indicators were screened by combining risk score with clinical characteristics, and a nomogram was created to forecast survival in GC patients. Further, in single-cell data analysis, cell clusters and cell subpopulations were yielded, followed by the completion of pseudo-time analysis. Furthermore, a more comprehensive immunological analysis was executed to uncover the relationship between GC and immunological characteristics. Ultimately, expression level of prognostic genes was validated through public datasets and qRT-PCR.ResultsA risk model including six prognostic genes (GPX3, GJA1, VCAN, RGS2, LOX, and CTHRC1) associated with mitochondria and macrophage polarisation was developed, which was efficient in forecasting the survival of GC patients. The GC patients were categorized into high-/low-risk subgroups in accordance with median risk score, with the high-risk subgroup having lower survival rates. Afterwards, a nomogram incorporating risk score and age was generated, and it had significant predictive value for predicting GC survival with higher predictive accuracy than risk model. Immunological analyses revealed showed higher levels of M2 macrophage infiltration in high-risk subgroup and the strongest positive correlation between risk score and M2 macrophages. Besides, further analyses demonstrated a better outcome for immunotherapy in low-risk patients. In single-cell and pseudo-time analyses, stromal cells were identified as key cells, and a relatively complete developmental trajectory existed for stromal C1 in three subclasses. Ultimately, expression analysis revealed that the expression trend of RGS2, GJA1, GPX3, and VCAN was consistent with the results of the TCGA-GC dataset.ConclusionOur findings demonstrated that a novel prognostic model constructed in accordance with six prognostic genes might facilitate the improvement of personalised prognosis and treatment of GC patients.

ObjectiveThe purpose of this study is to investigate potential associations between osteopenia, osteosarcopenia, and postoperative outcomes in patients with hepatobiliary-pancreatic cancer (HBPC).MethodsThree online databases, including Embase, PubMed, and the Cochrane Library, were thoroughly searched for literature describing the relationship between osteopenia, osteosarcopenia, and outcomes of surgical treatment of HBPC patients from the start of each database to September 29, 2023. The Newcastle-Ottawa Scale was used to rate the quality of the studies.ResultsThis analysis included a total of 16 articles with a combined patient cohort of 2,599 individuals. The results demonstrated that HBPC patients with osteopenia had significantly inferior OS (HR: 2.27, 95% CI: 1.70-3.03, p < 0.001) and RFS (HR: 1.96, 95% CI: 1.42-2.71, p < 0.001) compared to those without osteopenia. Subgroup analysis demonstrated that these findings were consistent across univariate and multivariate analyses, as well as hepatocellular carcinoma, biliary tract cancer, and pancreatic cancer. The risk of postoperative major complications was significantly higher in patients with osteopenia compared to those without osteopenia (OR: 1.66, 95% CI: 1.19-2.33, p < 0.001). Besides, we also found that the presence of osteosarcopenia in HBPC patients was significantly related to poorer OS (HR: 3.31, 95% CI: 2.00-5.48, p < 0.001) and PFS (HR: 2.50, 95% CI: 1.62-3.84, p < 0.001) in comparison to those without osteosarcopenia.ConclusionPreoperative osteopenia and osteosarcopenia can predict poorer OS and RFS with HBPC after surgery.

ObjectivesTo explore the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) on lung adenosquamous cell carcinoma (ASC) with EGFR mutation.MethodsEfficacy of EGFR-TKIs in the treatment of advanced or recurrent lung ASC with EGFR mutations was assessed retrospectively in 44 patients. Pooled analysis of 74 patients using EGFR-TKIs, including 30 patients selected from 11 publications, was conducted.ResultsIn our retrospective research, patients treated with EGFR-TKI in ASC with EGFR mutations had objective response rate (ORR) of 54.5%, disease control rate (DCR) of 79.5%, median progression free survival (mPFS) of 8.8 months, and median overall survival (mOS) of 19.43 months, respectively. A pooled analysis reveals ORR, DCR, mPFS, and mOS are, respectively, 63.4%, 85.9%, 10.00 months, and 21.37 months for ASC patients. In patients with deletions in exon 19 and exon 21 L858R mutations, mPFS (11.0 versus 10.0 months, P=0.771) and mOS (23.67 versus 20.33 months, P=0.973) were similar. Erlotinib or gefitinib-treated patients had an overall survival trend that was superior to that of icotinib-treated patients.ConclusionsASC harboring EGFR mutations can be treated with EGFR-TKI in a similar manner to Adenocarcinoma (ADC) harboring EGFR mutations. There is still a need for further investigation to identify the separate roles of ASC’s two components in treating EGFR.

Abstract Gefitinib is one of the most extensively utilized epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for treating advanced lung adenocarcinoma (LUAD) patients harboring EGFR mutation. However, the emergence of drug resistance significantly compromised the clinical efficacy of EGFR-TKIs. Gaining further insights into the molecular mechanisms underlying gefitinib resistance holds promise for developing novel strategies to overcome the resistance and improve the prognosis in LUAD patients. Here, we identified that the inhibitory efficacy of gefitinib on EGFR-mutated LUAD cells was partially dependent on the induction of ferroptosis, and ferroptosis protection resulted in gefitinib resistance. Among the ferroptosis suppressors, aldo-keto reductase family 1 member C1 (AKR1C1) exhibited significant upregulation in gefitinib-resistant strains of LUAD cells and predicted poor progression-free survival (PFS) and overall survival (OS) of LUAD patients who received first-generation EGFR-TKI treatment. Knockdown of AKR1C1 partially reversed drug resistance by re-sensitizing the LUAD cells to gefitinib-mediated ferroptosis. The decreased expression of miR-338-3p contributed to the aberrant upregulation of AKR1C1 in gefitinib-resistant LUAD cells. Furthermore, upregulated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) sponged miR-338-3p to neutralize its suppression on AKR1C1. Dual-luciferase reporter assay and miRNA rescue experiment confirmed the NEAT1_1/miR-338-3p/AKR1C1 axis in EGFR-mutated LUAD cells. Gain- and loss-of-function assays demonstrated that the NEAT1_1/miR-338-3p/AKR1C1 axis promoted gefitinib resistance, proliferation, migration, and invasion in LUAD cells. This study reveals the effects of NEAT1_1/miR-338-3p/AKR1C1 axis-mediated ferroptosis defence in gefitinib resistance in LUAD. Thus, targeting NEAT1_1/miR-338-3p/AKR1C1 axis might be a novel strategy for overcoming gefitinib resistance in LUAD harboring EGFR mutation.

Abstract Small bowel vascular malformation disease (SBVM) commonly causes obscure gastrointestinal bleeding (OGIB). However, the pathogenetic mechanism and the role of lncRNAs in SBVM remain largely unknown. Here, we found that hypoxia and low-glucose environments co-augment angiogenesis and existed in SBVM. Mechanistically, hypoxia and low-glucose environments supported angiogenesis via activation of hypoxia and glucose deprivation-induced lncRNA (HGDILnc1) transcription by increasing binding of the NeuroD1 transcription factor to the HGDILnc1 promoter. Raised HGDILnc1 acted as a suppressor of α-Enolase 1 (ENO1) small ubiquitin-like modifier modification (SUMOylation)-triggered ubiquitination, and an activator of transcription of Aldolase C (ALDOC) via upregulation of Histone H2B lysine 16 acetylation (H2BK16ac) level in the promoter of ALDOC, and consequently promoting glycolysis and angiogenesis. Moreover, HGDILnc1 was clinically positively correlated with Neurogenic differentiation 1 (NeuroD1), ENO1, and ALDOC in SBVM tissues, and could function as a biomarker for SBVM diagnosis and therapy. These findings suggest that hypoxia and low-glucose environments were present in SBVM tissues, and co-augmented angiogenesis. Hypoxia and low-glucose environments co-induced HGDILnc1, which is higher expressed in SBVM tissue compared with normal tissue, could promoted glycolysis and angiogenesis.

Abstract Bacillus cereus is a clinically significant foodborne pathogen that causes severe gastrointestinal and non-gastrointestinal disease. Cereolysin O (CLO) is a putative virulence factor of B. cereus, and its function remains to be investigated. In this study, we examined the biological activity of CLO from a deep sea B. cereus isolate. CLO was highly toxic to mammalian cells and triggered pyroptosis through NLRP3 inflammasome-mediated caspase 1 and gasdermin D activation. CLO-induced cell death involved ROS accumulation and K+ efflux, and was blocked by serum lipids. CLO bound specifically to cholesterol, and this binding was essential to CLO cytotoxicity. The structural integrity of the three tryptophan residues in the C-terminal undecapeptide was vital for CLO to interact with membrane lipids and cause membrane perforation. Taken together, these results provided new insights into the molecular mechanism of B. cereus CLO-mediated cytotoxicity.

Abstract Background Cancer-associated fibroblasts (CAFs) orchestrate a supportive niche that fuels cancer metastatic development in non-small cell lung cancer (NSCLC). Due to the heterogeneity and plasticity of CAFs, manipulating the activated phenotype of fibroblasts is a promising strategy for cancer therapy. However, the underlying mechanisms of fibroblast activation and phenotype switching that drive metastasis remain elusive. Methods The clinical implications of fibroblast activation protein (FAP)-positive CAFs (FAP+CAFs) were evaluated based on tumor specimens from NSCLC patients and bioinformatic analysis of online databases. CAF-specific circular RNAs (circRNAs) were screened by circRNA microarrays of primary human CAFs and matched normal fibroblasts (NFs). Survival analyses were performed to assess the prognostic value of circNOX4 in NSCLC clinical samples. The biological effects of circNOX4 were investigated by gain- and loss-of-function experiments in vitro and in vivo. Fluorescence in situ hybridization, luciferase reporter assays, RNA immunoprecipitation, and miRNA rescue experiments were conducted to elucidate the underlying mechanisms of fibroblast activation. Cytokine antibody array, transwell coculture system, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the downstream effectors that promote cancer metastasis. Results FAP+CAFs were significantly enriched in metastatic cancer samples, and their higher abundance was correlated with the worse overall survival in NSCLC patients. A novel CAF-specific circRNA, circNOX4 (hsa_circ_0023988), evoked the phenotypic transition from NFs into CAFs and promoted the migration and invasion of NSCLC in vitro and in vivo. Clinically, circNOX4 correlated with the poor prognosis of advanced NSCLC patients. Mechanistically, circNOX4 upregulated FAP by sponging miR-329-5p, which led to fibroblast activation. Furthermore, the circNOX4/miR-329-5p/FAP axis activated an inflammatory fibroblast niche by preferentially inducing interleukin-6 (IL-6) and eventually promoting NSCLC progression. Disruption of the intercellular circNOX4/IL-6 axis significantly suppressed tumor growth and metastatic colonization in vivo. Conclusions Our study reveals a role of the circRNA-induced fibroblast niche in tumor metastasis and highlights that targeting the circNOX4/FAP/IL-6 axis is a promising strategy for the intervention of NSCLC metastasis.

Abstract Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint. In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.

Abstract Hypoxia, which activates a variety of signaling pathways to enhance tumor cell growth and metabolism, is among the primary features of tumor cells. Hypoxia-inducible factors (HIFs) have a substantial impact on a variety of facets of tumor biology, such as epithelial-mesenchymal transition, metabolic reprogramming, angiogenesis, and improved radiation resistance. HIFs induce hypoxia-adaptive responses in tumor cells. Many academics have presented preclinical and clinical research targeting HIFs in tumor therapy, highlighting the potential applicability of targeted HIFs. In recent years, the discovery of numerous pharmacological drugs targeting the regulatory mechanisms of HIFs has garnered substantial attention. Additionally, HIF inhibitors have attained positive results when used in conjunction with traditional oncology radiation and/or chemotherapy, as well as with the very promising addition of tumor immunotherapy. Immune checkpoint inhibitors (CPIs), which are employed in a range of cancer treatments over the past decades, are essential in tumor immunotherapy. Nevertheless, the use of immunotherapy has been severely hampered by tumor resistance and treatment-related toxicity. According to research, HIF inhibitors paired with CPIs may be game changers for multiple malignancies, decreasing malignant cell plasticity and cancer therapy resistance, among other things, and opening up substantial new pathways for immunotherapy drug development. The structure, activation mechanisms, and pharmacological sites of action of the HIF family are briefly reviewed in this work. This review further explores the interactions between HIF inhibitors and other tumor immunotherapy components and covers the potential clinical use of HIF inhibitors in combination with CPIs.

Abstract Background Adoptive cell therapy has achieved great success in treating hematological malignancies. However, the production of chimeric antigen receptor T (CAR-T) cell therapy still faces various difficulties. Natural killer (NK)-92 is a continuously expandable cell line and provides a promising alternative for patient’s own immune cells. Methods We established CAR-NK cells by co-expressing natural killer group 2 member D (NKG2D) and IL-21, and evaluated the efficacy of NKG2D-IL-21 CAR-NK cells in treating lung cancer in vitro and in vivo. Results Our data suggested that the expression of IL-21 effectively increased the cytotoxicity of NKG2D CAR-NK cells against lung cancer cells in a dose-dependent manner and suppressed tumor growth in vitro and in vivo. In addition, the proliferation of NKG2D-IL-21 CAR-NK cells were enhanced while the apoptosis and exhaustion of these cells were suppressed. Mechanistically, IL-21-mediated NKG2D CAR-NK cells function by activating AKT signaling pathway. Conclusion Our findings provide a novel option for treating lung cancer using NKG2D-IL-21 CAR-NK cell therapy.

Abstract Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes is critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house and public cohorts, we investigated the expression features and immuno-correlations of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in a mouse model. We also developed a novel classifier combining B7-H3 and PD-L1 expression in TNBC. B7-H3 was revealed to be related to immuno-cold features and accumulated collagen in TNBC. In addition, targeting B7-H3 using the monoclonal antibody significantly suppressed mouse TNBC growth, reversed the armored-cold phenotype, and also boosted anti-PD-1 immunotherapy. In addition, patients with B7-H3 high and PD-L1 low expression showed the lowest anti-tumor immune infiltration, the highest collagen level, and the lowest therapeutic responses to multiple therapies, which mostly belong to armored-cold tumors. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression, which leads to a novel approach for the management of TNBC.

Abstract Background Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. Conclusions DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Abstract Heat shock proteins play crucial roles in various biochemical processes, encompassing protein folding and translocation. HSP90B1, a conserved member of the heat shock protein family, growing evidences have demonstrated that it might be closely associated with cancer development. In the present study, we employed multi-omics analyses and cohort validations to explore the dynamic expression of HSP90B1 in pan-cancer and comprehensively evaluate HSP90B1 as a novel biomarker that hold promise for precision cancer diagnostics and therapeutics. The results suggest HSP90B1 was highly expressed in various kinds of tumors, often correlating with a poor prognosis. Notably, methylation of HSP90B1 emerged as a protective factor in several cancer types. In immune infiltration analysis, the expression of HSP90B1 in most tumors showed a negative association with CD8 + T cells. HSP90B1 expression was positively correlated with microsatellite instability and tumor mutational burden. HSP90B1 expression was also discovered to be positively correlated with tumor metabolism, cell cycle-related pathways and the expression of immune checkpoint genes. The expression of HSP90B1 was mainly negatively correlated with immunostimulatory genes and positively correlated with immunosuppressive genes, as well as strongly correlated with chemokines and their receptor genes. In addition, the HSP90B1 inhibitor PU-WS13 demonstrated significant efficacy in suppressing cancer cell proliferation in both leukemic and solid tumor cells, and remarkably reduced the expression of the cancer cell surface immune checkpoint PD-L1. The single-cell RNA sequencing analysis further highlighted that HSP90B1 was significantly higher in tumor cells compared to surrounding cells, revealing a potential target therapeutic window. Taken together, HSP90B1 emerges as a promising avenue for breakthroughs in cancer diagnosis, prognosis and therapy. This study provides a rationale for HSP90B1 targeted cancer diagnosis and therapy in future.

Abstract Background Cancer associated fibroblasts (CAFs) can remodel tumor microenvironment by secreting exosomes. This study aimed to investigate the role of exosomes derived from cancer-associated fibroblasts in colorectal cancer (CRC) progression. Methods Circular RNA (circRNA) array was used to identify differentially expressed circRNAs in exosomes from normal fibroblasts (NFs) and CAFs, and confirmed one differentially expressed circRNA circ_0067557 by real-time PCR. The effect of circ_0067557 on proliferation, metastasis, chemoresistance and apoptosis was verified by wound heal, tranwell, CCK8, sphere-forming and flow cytometry assay. Results Circ_0067557 expression in exosomes from CAFs was higher than those from NFs. CAF-derived exosomes promoted the proliferation, migration, invasion and chemoresistance of CRC cells while suppressed apoptosis. Silencing of circ_0067557 inhibited malignant phenotypes of CRC cells by targeting Lin28A and Lin28B. Moreover, CAF-derived exosomes enhanced the growth of CRC xenograft tumors. Conclusion Circ_0067557/Lin28A and Lin28B signal axis may be a potential therapy target for CRC.

ABSTRACTColorectal cancer (CRC) is among the most common gastrointestinal malignancies worldwide. eIF3a is highly expressed in a variety of cancer types, yet its role in CRC remains unclear. We introduced ectopic eIF3a expression in CRC cells to investigate its relevance to various malignant behaviors. Further, we silenced eIF3a to explore its effect on tumor growth in a nude mouse tumor xenograft model. Finally, the molecular mechanisms through which eIF3a regulates malignancy in CRC cells were explored through bioinformatics analysis combined with the use of a specific PI3K inhibitor (LY294002). eIF3a was highly expressed in the peripheral blood and cancer tissue of CRC patients. Malignancy and tumor growth were significantly inhibited by silencing eIF3a, while overexpression promoted malignant behaviors, with a positive correlation between PI3K/AKT activation and eIF3a expression. Taken together, eIF3a plays an oncogenic role in CRC by regulating PI3K/AKT signaling and is a potential biomarker for CRC diagnosis and prognostic monitoring.

Abstract Malignant pleural mesothelioma (MPM) is a malignant tumor of the pulmonary pleural tissue for which there is a lack of effective targeted therapy. In this study, moderate to high V‐domain immunoglobulin T‐cell activation suppressor (VISTA) expression levels were observed in most MPM clinical tumor samples. We prepared two high‐affinity anti‐VISTA monoclonal antibodies (mAbs) and generated two novel VISTA‐targeted antibody‐drug conjugates (ADCs) by conjugating anti‐VISTA mAbs with the potent cytotoxic drug monomethyl auristatin E (MMAE). αV1‐MMAE and αV2‐MMAE showed potent killing effects to VISTA‐positive cell lines in vitro, with half‐maximal inhibitory concentration (IC50) of nanomolar levels. αV1‐MMAE and αV2‐MMAE were also able to significantly induce apoptosis and cause G2/M phase arrest in VISTA‐positive cells. In the VISTA‐positive human MPM xenograft model, both αV1‐MMAE and αV2‐MMAE showed significant antitumor activity, led to a significant survival advantage compared to mice in the control group, and effectively induced apoptosis in the tumor tissues of mice. In conclusion, we demonstrated that the novel VISTA‐targeted ADCs (αV1‐MMAE and αV2‐MMAE), especially αV1‐MMAE, had potent killing effects against VISTA‐positive MPM cells both in vitro and in vivo. Therefore, through further development, they may have the potential to become new drugs for the treatment of MPM.

Abstract Background Exosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non‐coding RNAs (lncRNAs) are implicated in tumorigenesis and progression. Aims The purpose of this study is to construction a exosomes‐related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC. Methods Data of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes‐related lncRNAs (ERLRs) from Top10 exosomes‐related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs‐based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high‐ and low‐risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients. Results A score consisting of 4ERLRs was identified, and patients with higher ERLRs‐based score tended to have a worse prognosis than those with lower ERLRs‐based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III‐IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa‐miR‐31‐5p/TLN2 axis. Conclusions Based on machine learning, a novel ERLRs‐based score was constructed for predicting the survival of ccRCC patients. The ERLRs‐based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa‐miR‐31‐5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.

Abstract Background Ovarian cancer is a common gynecological tumor with high malignant potential and poor prognosis. TRIM8, is involved in the development of various tumors, but its precise regulatory role in ovarian cancer is still unknown. Aims The aim of this study was to explore the specific mechanism by which TRIM8 regulates ovarian cancer. Materials and Methods We used bioinformatics analysis to screen for high expression of TRIM8 in ovarian cancer. The expression of TRIM8 in healthy and cancerous ovarian tissues was assessed by immunofluorescence. TRIM8 was silenced or overexpressed in ovarian cancer cell lines, with cell proliferation and migration evaluated by CCK8, transwell and clonal formation assays. The effect of TRIM8 on ovarian cancer cells in vivo was assessed by subcutaneous tumor formation experiments in nude mice. The potential interacting protein VDAC2 was identified by mass spectrometry. The mechanism underlying TRIM8 regulation of VDAC2 was evaluated by co‐immunoprecipitation and western blotting. Results TRIM8 was overexpressed in ovarian cancer. TRIM8 promoted the proliferation and migration of ovarian cancer cells in vitro and the growth of subcutaneous tumors in mice in vivo. TRIM8 interacted with VDAC2, weakened the stability of the protein, and promoted its polyubiquitination and subsequent degradation. Knockdown of VDAC2 increased the resistance of ovarian cancer cells to iron death, whereas overexpression of VDAC2 attenuated ovarian cancer progression induced by TRIM8 overexpression. Discussion TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation, these finding may provide new targets for the treatment of ovarian cancer. Conclusion TRIM8 degraded VDAC2 through the ubiquitination pathway, increased the resistance of ovarian cancer cells to iron death, and promoted the proliferation and migration of ovarian cancer.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed in advanced stages, necessitating pancreaticoduodenectomy (PD) as a primary therapeutic approach. However, PD surgery can engender intricate complications. Thus, understanding the factors influencing postoperative complications documented in electronic medical records and their impact on survival rates is crucial for improving overall patient outcomes.MethodsA total of 749 patients were divided into two groups: 598 (79.84%) chose the RPD (Robotic pancreaticoduodenectomy) procedure and 151 (20.16%) chose the LPD (Laparoscopic pancreaticoduodenectomy) procedure. We used correlation analysis, survival analysis, and decision tree models to find the similarities and differences about postoperative complications and prognostic survival.ResultsPancreatic cancer, known for its aggressiveness, often requires pancreaticoduodenectomy as an effective treatment. In predictive models, both BMI and surgery duration weigh heavily. Lower BMI correlates with longer survival, while patients with heart disease and diabetes have lower survival rates. Complications like delayed gastric emptying, pancreatic fistula, and infection are closely linked post-surgery, prompting conjectures about their causal mechanisms. Interestingly, we found no significant correlation between nasogastric tube removal timing and delayed gastric emptying, suggesting its prompt removal post-decompression.ConclusionThis study aimed to explore predictive factors for postoperative complications and survival in PD patients. Effective predictive models enable early identification of high-risk individuals, allowing timely interventions. Higher BMI, heart disease, or diabetes significantly reduce survival rates in pancreatic cancer patients post-PD. Additionally, there’s no significant correlation between DGE incidence and postoperative extubation time, necessitating further investigation into its interaction with pancreatic fistula and infection.

Abstract Background Consolidation therapy improves the duration of response among patients with primary central nervous system lymphoma (PCNSL). Lenalidomide maintenance has shown encouraging results in older patients with PCNSL. Herein, we performed a retrospective, single‐center analysis to evaluate the effect of lenalidomide maintenance on the duration of response in patients with newly‐diagnosed PCNSL. Methods Sixty‐nine adult patients with PCNSL who achieved complete remission or partial remission (PR) after induction therapy were enrolled. The median age of patients was 58.0 years. The maintenance group (n = 35) received oral lenalidomide (25 mg/day) for 21 days, every 28 days for 24 months; the observation group did not undergo any further treatment. Results After a median follow‐up of 32.6 months, the maintenance group experienced fewer relapse events. However, the median progression‐free survival (PFS) was similar between groups (36.1 vs. 30.6 months; hazard ratio, 0.78; 95% confidence interval, 0.446). Lenalidomide maintenance significantly improved PFS and overall survival (OS) only among patients who experienced PR after induction. The median duration of lenalidomide maintenance was 18 months; lenalidomide was well tolerated and minimally impacted the quality of life. Conclusions The present study was the first to evaluate lenalidomide maintenance as a frontline treatment among patients with PCNSL, PFS and OS did not improve, although the safety profile was satisfactory.

Objective To evaluate the effectiveness of oral probiotic supplements in patients undergoing immune checkpoint inhibitors (ICIs) for the treatment of advanced lung cancer. Methods This prospective real-world study enrolled patients with advanced lung cancer who were receiving ICIs as part of their treatment. The patients were divided into 2 groups: Group OPS received oral probiotic supplements along with ICIs, while Group C did not. The primary endpoint was progression-free survival (PFS). The secondary outcome measure was the objective response rate (ORR). Results A total of 253 patients were included in the study, with 71 patients in Group OPS and 182 patients in the control group (Group C). No significant differences were observed in the median PFS between the 2 groups for all patients. However, for small cell lung cancer (SCLC) patients, the median PFS was significantly better in the Group OPS compared to the Group C (11.1 months vs 7.0 months, P = .049). No significant differences were observed in median PFS for the non-small cell lung cancer (NSCLC) cohort between the 2 groups, but a trend towards better median PFS in Group OPS was noticed (16.5 months vs 12.3 months, P = .56). The ORR for the entire cohort was 58.0%. Conclusion Oral probiotics supplements in combination with ICIs included regimen may improve the outcome in patients with advanced SCLC. The above points should be proved by further study.

Abstract Background The death burden attributable to modifiable risk factors is key to colorectal cancer (CRC) prevention. This study aimed to assess the prevalence and regional distribution of attributable CRC death burden worldwide from 1990 to 2019. Methods We extracted data from the Global Burden of Disease Study in 2019 and assessed the mortality, age‐standardized death rate (ASDR), population attributable fractions, and time trend in CRC attributable to risk factors by geography, socio‐demographic index (SDI) quintile, age, and sex. Results Over the past 30 years, from high to low SDI region, the number of deaths increased by 46.56%, 103.55%, 249.64%, 231.89%, 163.11%, and the average annual percentage change (AAPC) for ASDR were −1.06%, −0.01%, 1.32%, 1.19%, and 0.65%, respectively. ASDR in males was 1.88 times than in females in 2019; ASDR in males showed an increasing trend (AAPC 0.07%), whereas ASDR in females showed a decreasing trend (AAPC −0.69%) compared to figures in 1990. In 2019, from high to low SDI region, the 15–49 age group accounted for 3%, 6%, 10%, 11%, and 15% of the total population; dietary and metabolic factors contributed 43.4% and 20.8% to CRC‐attributable death worldwide. From high to low SDI region, ASDRs caused by dietary and metabolic factors increased by −23.4%, −5.5%, 25.8%, 29.1%, 13.5%, and 1.4%, 33.3%, 100.8%, 128.4%, 77.7% respectively, compared to 1990. Conclusions The attributable CRC death burden gradually shifted from higher SDI to lower SDI regions. The limitation in males was more significant, and the gap is expected to be further expanded. In lower SDI regions, the death burden tended to affect younger people. The leading cause of CRC‐attributable deaths was the inadequate control of dietary and metabolic risk factors.

Abstract CAR-T cell therapy did not achieve the desired efficacy in some patients with diffuse large B-cell lymphoma (DLBCL). We conducted single-cell RNA and TCR sequencing as well as methylation chip profiling of peripheral blood samples in DLBCL patients. Patients who achieved complete remission (CR) showed an upward trend in T-cell levels, especially CD8-effector T cells. The responders exhibited T-cell clone expansion, more active T-cell transformation, and frequent cell communication. Highly expressed genes in the CR group were enriched in functions like leukocyte-mediated cytotoxicity and activation of immune response, while the non-CR group was enriched in pathways related to DNA damage and P53-mediated intrinsic apoptotic. More differentially methylated probes (DMPs) were identified in the baseline of the non-CR group (779 vs 350). GSEA analysis revealed that the genes annotated by DMPs were associated with cellular immune functions in T cells, including the generation of chemokines, leukocyte-mediated cytotoxicity, and cell-killing functions. The genes with low expression in the non-CR group exhibited a high methylation status. There is heterogeneity in the cellular, molecular, and epigenetic characteristics of host T cells in patients with different clinical outcomes. Intrinsic defects in T cells are important factors leading to poor efficacy of CAR-T therapy.

Abstract Background Fibroblasts, especially cancer-associated fibroblasts (CAFs), represent the predominant stromal cell population in the tumor microenvironment and have an important function in tumorigenesis by interacting with tumor cells. However, their interaction remains elusive in an inflammatory tumor microenvironment induced by Helicobacter pylori (H. pylori). Methods The expression of Serpin family E member 1 (Serpin E1) was measured in fibroblasts with or without H. pylori infection, and primary gastric cancer (GC) cells. Serpin E1 knockdown and overexpression fibroblasts were generated using Serpin E1 siRNA or lentivirus carrying Serpin E1. Co-culture models of fibroblasts and GC cells or human umbilical vein endothelial cells (HUVECs) were established with direct contact or the Transwell system. In vitro functional experiments and in vivo tumorigenesis assay were employed to study the malignant behaviors of GC cells interacting with fibroblasts. ELISA was used for quantifying the levels of Serpin E1 and VEGFA in the culture supernatant. The tube formation capacity of HUVECs was assessed using a tube formation assay. Recombinant human Serpin E1 (recSerpin E1), anti-Serpin E1 antibody, and a MAPK pathway inhibitor were utilized to treat HUVECs for elucidating the underlying molecular mechanisms. Results Serpin E1 was predominantly expressed in gastric CAFs. H. pylori infection significantly enhanced the expression and secretion of Serpin E1 by CAFs. Both fibroblast-derived Serpin E1 and recSerpin E1 enhanced the growth, invasion, and migration of GC cells, along with increased VEGFA expression and tube formation in HUVECs. Furthermore, the co-inoculation of GC cells and fibroblasts overexpressing Serpin E1 triggered the expression of Serpin E1 in cancer cells, which facilitated together xenograft tumor growth and peritoneal dissemination of GC cells in nude mice, with an increased expression of Ki67, Serpin E1, CD31 and/or VEGFA. These processes may be mediated by Serpin E1-induced migration and p38 MAPK/VEGFA-mediated angiogenesis of HUVECs. Conclusion H. pylori infection induces Serpin E1 expression in fibroblasts, subsequently triggering its expression in GC cells through their interaction. Serpin E1 derived from these cells promotes the migration and p38 MAPK/VEGFA-mediated angiogenesis of HUVECs, thereby facilitating GC growth and peritoneal metastasis. Targeting Serpin E1 signaling is a potential therapy strategy for H. pylori-induced GC.

Abstract Background Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC. Methods We conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Between January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3–8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5–7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83–1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62–1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group. Conclusions Our research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.

During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase‐like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodelling. In this study, protein–protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of oesophageal squamous cell carcinoma (ESCC) cells, as well as tumour growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumour growth. Co‐overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumour cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican‐1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3β signalling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumour progression through multiple mechanisms and could be a potential therapeutic target.

Objective: Transcriptomic characteristics and prognosis of tertiary lymphoid structures (TLS) and infiltrating B cells in nasopharyngeal carcinoma (NPC) remain unclear. Here, NPC transcriptomic data and clinical samples were used to investigate the role of infiltrating B cells and TLS in NPC. Methods: We investigated the gene expression and infiltrating immune cells of NPC patients and further investigated the clinical relevance of B cell and TLS signatures. Transcriptional features of infiltrating B cell subsets were revealed by single-cell RNA sequencing (scRNA-seq) analysis. Immunohistochemical (IHC) and HE staining were performed to validate the clinical relevance of infiltrating B cells and TLS in NPC samples. Results: 27 differentially expressed immune-related genes (IRGs) associated with prognosis were identified, including B cell marker genes CD19 and CD79B. The higher B cells and TLS signature scores were associated with better outcomes and early pathological staging in 88 NPC patients. ScRNA-seq identified five distinct B cell subsets in NPC, including the BC-4 cluster associated with poor outcomes and the BC-0 cluster associated with better outcomes. EBV infection was positively associated with the formation of TLS. Furthermore, experimental results showed that the infiltration of B cells in NPC tissues was higher than that of normal tissues, and the density of TLS in an early stage of NPC was higher than that in advanced-stage TLS. Conclusion: Our findings demonstrate the functional importance of distinct B cell subsets in the prognosis of NPC. Additionally, we confirmed that B cells and TLS may serve as prognostic biomarkers of survival for NPC patients.

Primary malignant pericardial mesothelioma (PMPM) is a rare pericardial malignant tumor. Most manifestations of PMPM are localized or diffuse masses surrounding the heart. The prognosis of diffuse PMPM is poor due to the difficulty of surgical resection. Although the edge of localized PMPM is clear and can be easily resected, the diagnosis of this disease is difficult. Timely diagnosis and proper treatment are key to a good prognosis. Here, we report a patient with localized PMPM and describe the method for the diagnosis of this disease.

BackgroundBeing the most widely used biomarker for immunotherapy, the microsatellite status has limitations in identifying all patients who benefit in clinical practice. It is essential to identify additional biomarkers to guide immunotherapy. Aberrant DNA methylation is consistently associated with changes in the anti-tumor immune response, which can promote tumor progression. This study aims to explore immunotherapy biomarkers for colon cancers from the perspective of DNA methylation.MethodsThe related data (RNA sequencing data and DNA methylation data) were obtained from The Cancer Genome Atlas (TCGA) and UCSC XENA database. Methylation-driven genes (MDGs) were identified through the Pearson correlation analysis. Unsupervised consensus clustering was conducted using these MDGs to identify distinct clusters of colon cancers. Subsequently, we evaluated the immune status and predicted the efficacy of immunotherapy by tumor immune dysfunction and exclusion (Tide) score. Finally, The Quantitative Differentially Methylated Regions (QDMR) software was used to identify the specific DNA methylation markers within particular clusters.ResultsA total of 282 MDGs were identified by integrating the DNA methylation and RNA-seq data. Consensus clustering using the K-means algorithm revealed that the optimal number of clusters was 4. It was revealed that the composition of the tumor immune microenvironment (TIME) in Cluster 1 was significantly different from others, and it exhibited a higher level of tumor mutation burdens (TMB) and stronger anti-tumor immune activity. Furthermore, we identified three specific hypermethylation genes that defined Cluster 1 (PCDH20, APCDD1, COCH). Receiver operating characteristic (ROC) curves demonstrated that these specific markers could effectively distinguish Cluster 1 from other clusters, with an AUC of 0.947 (95% CI 0.903-0.990). Finally, we selected clinical samples for immunohistochemical validation.ConclusionIn conclusion, through the analysis of DNA methylation, consensus clustering of colon cancer could effectively identify the cluster that benefit from immunotherapy along with specific methylation biomarkers.

Abstract Background Lymph node metastasis (LNM) significantly impacts the prognosis of individuals diagnosed with cervical cancer, as it is closely linked to disease recurrence and mortality, thereby impacting therapeutic schedule choices for patients. However, accurately predicting LNM prior to treatment remains challenging. Consequently, this study seeks to utilize digital pathological features extracted from histopathological slides of primary cervical cancer patients to preoperatively predict the presence of LNM. Methods A deep learning (DL) model was trained using the Vision transformer (ViT) and recurrent neural network (RNN) frameworks to predict LNM. This prediction was based on the analysis of 554 histopathological whole‐slide images (WSIs) obtained from Qilu Hospital of Shandong University. To validate the model's performance, an external test was conducted using 336 WSIs from four other hospitals. Additionally, the efficiency of the DL model was evaluated using 190 cervical biopsies WSIs in a prospective set. Results In the internal test set, our DL model achieved an area under the curve (AUC) of 0.919, with sensitivity and specificity values of 0.923 and 0.905, respectively, and an accuracy (ACC) of 0.909. The performance of the DL model remained strong in the external test set. In the prospective cohort, the AUC was 0.91, and the ACC was 0.895. Additionally, the DL model exhibited higher accuracy compared to imaging examination in the evaluation of LNM. By utilizing the transformer visualization method, we generated a heatmap that illustrates the local pathological features in primary lesions relevant to LNM. Conclusion DL‐based image analysis has demonstrated efficiency in predicting LNM in early operable cervical cancer through the utilization of biopsies WSI. This approach has the potential to enhance therapeutic decision‐making for patients diagnosed with cervical cancer.

Abstract Background Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed to unmask the underlying roles and molecular mechanisms of circular RNAs. In the current study, our findings showed that circXRN2 suppresses tumor progression driven by histone lactylation by activating the Hippo pathway in human bladder cancer. Methods RNA immunoprecipitation (RIP) followed by circRNA sequencing confirmed circXRN2 as the research object. Overexpression of circXRN2 and knockdown of TAZ/YAP further verified the biological functions in T24 and TCCSUP cells. RIP, immunoprecipitation and coimmunoprecipitation were used to elucidate the interaction between circXRN2 and LATS1. A Seahorse metabolic analyzer was used to determine the glycolytic rate. Cleavage under targets and Tagmentation (CUT&Tag) and chromatin immunoprecipitation (ChIP) were employed to ensure the regulatory roles of H3K18 lactylation in the transcriptional activity of LCN2. Results CircXRN2 is aberrantly downregulated in bladder cancer tissues and cell lines. CircXRN2 inhibits the proliferation and migration of tumor cells both in vitro and in vivo. In addition, circXRN2 serves as a negative regulator of glycolysis and lactate production. Mechanistically, circXRN2 prevents LATS1 from SPOP-mediated degradation by binding to the SPOP degron and then activates the Hippo signaling pathway to exert various biological functions. The circXRN2-Hippo pathway regulatory axis further modulates tumor progression by inhibiting H3K18 lactylation and LCN2 expression in human bladder cancer. Conclusions CircXRN2 suppresses tumor progression driven by H3K18 lactylation by activating the Hippo signaling pathway in human bladder cancer. Our results indicated novel therapeutic targets and provided promising strategies for clinical intervention in human bladder cancer.

Abstract Background After the standardization, recording and follow‐up of imatinib use that significantly prolongs survival of gastrointestinal stromal tumors (GISTs), a comprehensive reassessment of the prognosis of GISTs is necessary and more conductive to treatment options. Methods A total of 2185 GISTs between 2013 and 2016 were obtained from the Surveillance, Epidemiology, and End Results database and comprised our training (n = 1456) and internal validation cohorts (n = 729). The risk factors extracted from univariate and multivariate analyses were used to establish a predictive nomogram. The model was evaluated and tested in the validation cohort internally and in 159 patients with GIST diagnosed between January 2015 and June 2017 in Xijing Hospital externally. Results The median OS was 49 months (range, 0–83 months) in the training cohort and 51 months (0–83 months) in the validation cohort. The concordance index (C‐index) of the nomogram was 0.777 (95% CI, 0.752–0.802) and 0.7787 (0.7785, bootstrap corrected) in training and internal validation cohorts, respectively, and 0.7613 (0.7579, bootstrap corrected) in the external validation cohort. Receiver operating characteristic curves and calibration curves for 1‐, 3‐, and 5‐year overall survival (OS) showed a high degree of discrimination and calibration. The area under the curve showed that the new model performed better than the TNM staging system. In addition, the model could be dynamically visualized on a webpage. Conclusion We developed a comprehensive survival prediction model for assessing the 1‐, 3‐ and 5‐year OS of patients with GIST in the postimatinib era. This predictive model outperforms the traditional TNM staging system and sheds light on the improvement of the prognostic prediction and the selection of treatment strategies for GISTs.

Abstract Background Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. Methods This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Results Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6–17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5–34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5–18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). Conclusions Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. Trial registration ClinicalTrials.gov identifier: NCT03736837.

Abstract Despite the benefit with cancer immunotherapies in clinical implication, immunotherapeutic resistance occurred in many patients and the mechanism remains unknown. Increasing evidence has revealed that cell‐intrinsic programmed cell death ligand 1 (PD‐L1) may play a non‐negotiable part in immunotherapeutic resistance. Our present study aimed to elucidate the immune‐independent acquired resistance mechanism to PD‐L1 antibody. We found elevated PD‐L1 expression induced by PD‐L1 antibodies in cancer cell and vascular endothelial cells (VECs) with substantially acquired resistance to PD‐L1 antibodies. Moreover, proliferation of resistant cells was accelerated and the apoptosis was reduced in the absence of immune compared with parental cells. Subsequently, we confirmed that the activation of the PI3K/AKT pathway is involved in the upregulation of PD‐L1 expression. Finally, we found that low dose of anlotinib downregulated PD‐L1 expression only in VECs via inhibiting the PI3K/AKT pathway; however, the same effect was not observed in cancer cells. To sum up, our findings revealed that upregulation of PD‐L1 via activation of the PI3K/AKT signal pathway may promote acquired resistance to PD‐L1 antibodies in an immune‐independent manner. Significance These findings provide new mechanisms of immunotherapeutic resistance and effective evidence of anlotinib combined with immunotherapy.

Abstract Background The clinical effect of postoperative radiotherapy (PORT) in non‐malignant meningioma (NMM) has not been well explored. Methods A total of 8629 patients with NMM (surgery alone group: n = 7716, postoperative radiotherapy group: n = 913) were obtained from the Surveillance, Epidemiology, and End Results database. Patient profiles were matched by 1:1 propensity score matching (PSM). Logistic regression analysis was performed to identify factors associated with PORT versus surgery alone (SA). Univariate and multivariate Cox regression analyses determined prognostic variables with overall survival (OS) in NMM. Subgroup analyses were performed with Cox proportional hazards regression models. Results All the SA (n = 7716) and PORT (n = 913) groups were included. Women with PORT (66.3%) and SA (70.9%) were almost twice as likely as men, and tumors with benign behaviors in the SA group were almost seven times more frequent than those with malignant characteristics. We explored the demographic, clinical characteristics, and prognostic factors in NMM. Laterality, surgery, tumor size, diagnosis year, age, and tumor behavior were associated with PORT versus SA. Patients treated with PORT had better OS than those treated with SA (p = 0.03). After PSM, PORT remained comparable to SA (hazard ratio 0.56, 95% confidence interval 0.35–0.88, p = 0.013). In the subgroup analysis of PORT treatment, borderline malignant behavior increased the death risk by 23%, while other variables did not have a significant clinical benefit (p > 0.05). Conclusions Borderline malignant behavior should be considered seriously, and the PORT regimen should be actively implemented for patients with benign meningiomas.

Abstract Hepatocellular carcinoma (HCC) is a common malignant tumor with insidious early symptoms, easy metastasis, postoperative recurrence, poor drug efficacy, and a high drug resistance rate when surgery is missed, leading to a low 5‐year survival rate. Research on the pathogenesis and drugs is particularly important for clinical treatment. Animal models are crucial for basic research, which is conducive to studying pathogenesis and drug screening more conveniently and effectively. An appropriate animal model can better reflect disease occurrence and development, and the process of anti‐tumor immune response in the human body. This review summarizes the classification, characteristics, and advances in experimental animal models of HCC to provide a reference for researchers on model selection.

Abstract Cardiovascular diseases (CVDs) such as atherosclerosis, myocardial remodeling, myocardial ischemia-reperfusion (I/R) injury, heart failure, and oxidative stress are among the greatest threats to human health worldwide. Cardiovascular pathogenesis has been studied for decades, and the influence of epigenetic changes on CVDs has been extensively studied. Post-translational modifications (PTMs), including phosphorylation, glycosylation, methylation, acetylation, ubiquitination, ubiquitin-like and nitrification, play important roles in the normal functioning of the cardiovascular system. Over the past decade, with the application of high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), an increasing number novel acylation modifications have been discovered, including propionylation, crotonylation, butyrylation, succinylation, lactylation, and isonicotinylation. Each change in protein conformation has the potential to alter protein function and lead to CVDs, and this process is usually reversible. This article summarizes the mechanisms underlying several common PTMs involved in the occurrence and development of CVDs.