A mild and efficient closed-loop recycling strategy for spent lithium-ion battery.

As lithium metal resource supply and demand stabilize and prices decrease, the efficient recovery of valuable metals other than lithium from spent lithium-ion batteries is receiving increasing attention. Currently, challenges remain in the selective lithium recovery efficiency and the high cost of regenerating valuable metal slag after lithium extraction, particularly for spent ternary cathode materials. To address these challenges, this study introduces a closed-loop recovery process for spent ternary cathode materials, employing sulfur-assisted roasting to achieve efficient lithium extraction and high-value direct regeneration of ternary leaching residues. At moderate temperatures (500 â„ƒ), LiNixCoyMn1-x-yO2 (NCM) materials undergo a directional transformation of lithium to Li2SO4 in synergy with sulfur and oxygen, achieving a lithium leaching extraction rate of 98.91 %. Additionally, the relatively mild reaction conditions preserve the secondary spherical morphology and uniform distribution of NiCoMn-based oxide residue without introducing adverse impurities, ensuring the successful regeneration of high-value NCM cathode materials (R-NCM). The R-NCM material exhibits good discharge capacity (144.3 mA·h/g at 1 C) and relatively stable cycling performance, with a capacity retention rate of 80 % after 150 cycles. This work provides a viable pathway for the efficient and environmental-friendly pyrometallurgical closed-loop recovery of spent lithium-ion batteries.

Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

Tumor-derived extracellular vesicle proteins as new biomarkers and targets in precision oncology.

Extracellular vesicles (EVs) are important carriers of signaling molecules, such as nucleic acids, proteins, and lipids, and have become a focus of increasing interest due to their numerous physiological and pathological functions. For a long time, most studies on EV components focused on noncoding RNAs; however, in recent years, extracellular vesicle proteins (EVPs) have been found to play important roles in diagnosis, treatment, and drug resistance and thus have been considered favorable biomarkers and therapeutic targets for various tumors. In this review, we describe the general protocols of research on EVPs and summarize their multifaceted roles in precision medicine applications, including cancer diagnosis, dynamic monitoring of therapeutic efficacy, drug resistance research, tumor microenvironment interaction research, and anticancer drug delivery.

Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a poor-prognostic cancer type with extensive intra- and inter-patient heterogeneity in both genomic variations and tumor microenvironment (TME). However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2, accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the esophagus. Interestingly, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+ T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted therapy. Collectively, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

Diagnostic and predictive significance of the ferroptosis-related gene TXNIP in lung adenocarcinoma stem cells based on multi-omics.

BACKGROUND: Lung cancer stands as the foremost cause of cancer-related fatalities globally. The presence of cancer stem cells (CSCs) poses a challenge, rendering current targeted tumor therapies ineffective. This study endeavors to investigate a novel therapeutic approach focusing on ferroptosis and delves into the expression of ferroptosis-related genes within lung CSCs. METHODS: We systematically examined RNA-seq datasets derived from lung tumor cells (LTCs) and lung cancer stem cells (LSCs), as previously investigated in our research. Our focus was on analyzing differentially expressed genes (DEGs) related to ferroptosis. Utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), we conducted functional analysis of these ferroptosis-related DEGs. Additionally, we employed protein‒protein interaction networks to identify hub genes. LC‒MS/MS analysis of LTCs and LSCs was conducted to pinpoint the crucial ferroptosis-related gene-thioredoxin-interacting protein (TXNIP).Further, we delved into the immune cell infiltration landscape of LTCs and LSCs, examining the correlation between TXNIP and lung adenocarcinoma (LUAD) using data from The Cancer Genome Atlas (TCGA) database. To complement these findings, we measured the expression levels of TXNIP, glutathione peroxidase 4(GPX4), nuclear receptor coactivator 4 (NCOA4) in LUAD tissues through immunohistochemistry (IHC) staining. RESULTS: A total of 651 DEGs were identified, with 17 of them being ferroptosis-related DEGs. These seventeen genes were categorized into four groups: driver genes, suppressor genes, unclassified genes, and inducer genes. Enrichment analysis revealed significant associations with oxidative stress, cell differentiation, tissue development, and cell death processes. The RNA-seq analysis demonstrated consistent gene expression patterns with protein expression, as evidenced by mass spectrometry analysis. Among the identified genes, SFN and TXNIP were singled out as hub genes, with TXNIP showing particularly noteworthy expression. The expression of the ferroptosis-related gene TXNIP exhibited correlations with the presence of an immunosuppressive microenvironment, TNM stages, and the degree of histological differentiation.Also, the ferroptosis-markers GPX4 and NCOA4 displayed correlations with LUAD. This comprehensive analysis underscores the significance of TXNIP in the context of ferroptosis-related processes and their potential implications in cancer development and progression. CONCLUSION: The investigation conducted in this study systematically delved into the role of the ferroptosis-related gene TXNIP in Lung CSCs. The identification of TXNIP as a potentially valuable biomarker in this context could have significant implications for refining prognostic assessments and optimizing therapeutic strategies for advanced lung cancer.

Leveraging new methods for comprehensive characterization of mitochondrial DNA in esophageal squamous cell carcinoma.

BACKGROUND: Mitochondria play essential roles in tumorigenesis; however, little is known about the contribution of mitochondrial DNA (mtDNA) to esophageal squamous cell carcinoma (ESCC). Whole-genome sequencing (WGS) is by far the most efficient technology to fully characterize the molecular features of mtDNA; however, due to the high redundancy and heterogeneity of mtDNA in regular WGS data, methods for mtDNA analysis are far from satisfactory. METHODS: Here, we developed a likelihood-based method dMTLV to identify low-heteroplasmic mtDNA variants. In addition, we described fNUMT, which can simultaneously detect non-reference nuclear sequences of mitochondrial origin (non-ref NUMTs) and their derived artifacts. Using these new methods, we explored the contribution of mtDNA to ESCC utilizing the multi-omics data of 663 paired tumor-normal samples. RESULTS: dMTLV outperformed the existing methods in sensitivity without sacrificing specificity. The verification using Nanopore long-read sequencing data showed that fNUMT has superior specificity and more accurate breakpoint identification than the current methods. Leveraging the new method, we identified a significant association between the ESCC overall survival and the ratio of mtDNA copy number of paired tumor-normal samples, which could be potentially explained by the differential expression of genes enriched in pathways related to metabolism, DNA damage repair, and cell cycle checkpoint. Additionally, we observed that the expression of CBWD1 was downregulated by the non-ref NUMTs inserted into its intron region, which might provide precursor conditions for the tumor cells to adapt to a hypoxic environment. Moreover, we identified a strong positive relationship between the number of mtDNA truncating mutations and the contribution of signatures linked to tumorigenesis and treatment response. CONCLUSIONS: Our new frameworks promote the characterization of mtDNA features, which enables the elucidation of the landscapes and roles of mtDNA in ESCC essential for extending the current understanding of ESCC etiology. dMTLV and fNUMT are freely available from https://github.com/sunnyzxh/dMTLV and https://github.com/sunnyzxh/fNUMT , respectively.

Genome-wide identification of the key kinesin genes during fiber and boll development in upland cotton (Gossypium hirsutum L.).

Kinesin is a kind of motor protein, which interacts with microtubule filaments and regulates cellulose synthesis. Cotton fiber is a natural model for studying the cellular development and cellulose synthesis. Therefore, a systematic research of kinesin gene family in cotton (Gossypium spp.) will be beneficial for both understanding the function of kinesin protein and assisting the fiber improvement. Here, we aimed to identify the key kinesin genes present in cotton by combining genome-wide expression profile data, association mapping, and public quantitative trait loci (QTLs) in upland cotton (G. hirsutum L.). Results showed that 159 kinesin genes, including 15 genes of the kinesin-13 gene subfamily, were identified in upland cotton; of which 157 kinesin genes can be traced back to the diploid ancestors, G. raimondii and G. arboreum. Using a combined analysis of public QTLs and genome-wide expression profile information, there were 29 QTLs co-localized together with 28 kinesin genes in upland cotton, including 10 kinesin-13 subfamily genes. Genome-wide expression profile data indicated that, among the 28 co-localized genes, seven kinesin genes were predominantly expressed in fibers or ovules. By association mapping analysis, 30 kinesin genes were significantly associated with three fiber traits, among which a kinesin-13 gene, Ghir_A11G028430, was found to be associated with both cotton boll length and lint weight, and one kinesin-7 gene, Ghir_D04G017880 (Gh_Kinesin7), was significantly associated with fiber strength. In addition, two missense mutations were identified in the motor domain of the Gh_Kinesin7 protein. Overall, the kinesin gene family seemingly plays an important role in cotton fiber and boll development. The exploited kinesin genes will be beneficial for the genetic improvement of fiber quality and yield.

Percutaneous Nephrolithotomy Versus Open Surgery in the Treatment of Urinary Calculi.

Objective: To evaluate the effectiveness of percutaneous nephrolithotomy (PCNL) compared with open surgery for urinary stone removal. Methods: A total of 95 patients with urinary stones were screened for eligibility between October 2020 and December 2021. After excluding 5 patients who revoked their consent, 90 patients were randomized to receive either traditional open surgery (traditional group) or PCNL (PCNL group), with 45 patients in each group. In addition, the two groups received Shugan Qingre Tonglin decoction twice daily for 2 weeks. Outcome measures included intraoperative indexes, stone removal rate, postoperative healing, and quality of life. Results: PCNL resulted in significantly better intraoperative indexes (95% CI, 0.49-1.11; P < .001), lower creatinine concentration (95% CI, 0.59-1.61; P < .001), and higher glomerular filtration rate (95% CI, 2.43-2.91; P < .001) compared with traditional open surgery. Patients in the PCNL group had a significantly higher stone removal rate (95% CI, 1.09-2.51; P < .001) and a lower incidence of adverse events (95% CI, 0.69-1.87; P < .001) compared with those receiving traditional open surgery. Patients in the PCNL group had significantly higher quality of life (95% CI, 1.39-2.81; P < .001) and significantly higher maximum urinary flow rate (95% CI, 1.36-2.61; P < .001) than those in the traditional group at 1 month and 3 months after treatment. Conclusion: PCNL provides better postoperative renal function improvement, enhances the postoperative recovery of patients with urinary stones, and features manageable safety compared with traditional open surgery. The benefits of PCNL make it a promising technique for the clinical management of urinary stones. Its minimally invasive nature reduces patient discomfort, promotes faster recovery, and improves overall patient satisfaction. The superior outcomes of PCNL in terms of renal function improvement and postoperative recovery suggest that it is a viable alternative to traditional open surgery. Further research and clinical trials are warranted to validate these findings and establish PCNL as a widely adopted approach in the field of urology.

Corrigendum to "SOX8 promotes tumor growth and metastasis through FZD6-dependent Wnt/ß-catenin signaling in colorectal carcinoma" [Heliyon 9(12) (December 2023) e22586].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e22586.].

Genome-wide identification of the key Kinesin genes during fiber and boll development in upland cotton (Gossypium hirsutum L).

Kinesin is a kind of motor protein, which interacts with microtubule filaments and regulates cellulose synthesis. Cotton fiber is a natural model for studying the cellular development and cellulose synthesis. Therefore, a systematic research of Kinesin gene family in cotton (Gossypium spp.) will be beneficial for both understanding the function of Kinesin protein and assisting the fiber improvement. Here, we aimed to identify the key Kinesin genes present in cotton by combining genome-wide expression profile data, association mapping, and public quantitative trait loci (QTLs) in upland cotton (Gossypium hirsutum L.). Results showed that 159 Kinesin genes, including 15 genes of the Kinesin-13 gene subfamily, were identified in upland cotton; of which 157 Kinesin genes can be traced back to the diploid ancestors, G. raimondii and G. arboreum. Using a combined analysis of public QTLs and genome-wide expression profile information, there were 29 QTLs co-localized together with 28 Kinesin genes in upland cotton, including 10 Kinesin-13 subfamily genes. Genome-wide expression profile data indicated that, among the 28 co-localized genes, seven Kinesin genes were predominantly expressed in fibers or ovules. By association mapping analysis, 30 Kinesin genes were significantly associated with three fiber traits, among which a Kinesin-13 gene, Ghir_A11G028430, was found to be associated with both cotton boll length and lint weight, and one Kinesin-7 gene, Ghir_D04G017880 (Gh_Kinesin7), was significantly associated with fiber strength. In addition, two missense mutations were identified in the motor domain of the Gh_Kinesin7 protein. Overall, the Kinesin gene family seemingly plays an important role in cotton fiber and boll development. The exploited Kinesin genes will be beneficial for the genetic improvement of fiber quality and yield.

All-element recovery and regeneration of mixed LiNixCoyMn1-x-yO2/LiFePO4 cathode materials by synergistic redox processes.

Given the rising lithium-ion battery retirement trend, there is a pressing need for a sustainable, cost-effective, versatile, and industrially viable positive active powder reprocessing method. The current treatment methods require significant amounts of acids, reducing agents, and other additives, resulting in increased treatment expenses and detrimental environmental consequences. This paper proposes a synergistic redox strategy, based on thermodynamic calculations of potential self-promoting reactions in mixed LFP/NCM systems, for the recovery of spent LFP and NCM batteries without the need for additional agents in a milder acidic atmosphere. In this cooperative redox strategy, the spontaneous extraction and oxidation of Fe2+ to Fe3+ took place within the acidic solution atmosphere encapsulating LFP. Simultaneously, NCM underwent further reduction, yielding Ni2+ and Fe2+, thereby enabling the proficient dissolution and segregation of lithium and transition metal ions. The leaching rate of lithium, nickel, cobalt and manganese was close to 100% when the reaction was carried out at 20 °C for 40 min. The final raw material was reprepared into a battery with a capacity of 168.8 mA h g-1 at 1C, and the cycle retention rate was 76.78% after 300 cycles. Regenerating FPO into LFP cathode material achieves closed-loop recycling of all elements and generates 12% higher profits compared to separate processes. Our method proposes a zero-additive battery recycling process and successfully explains the intrinsic redox process.

Anticancer effect of hUC-MSC-derived exosome-mediated delivery of PMO-miR-146b-5p in colorectal cancer.

Antisense oligonucleotide (ASO) is a novel therapeutic platform for targeted cancer therapy. Previously, we have demonstrated that miR-146b-5p plays an important role in colorectal cancer progression. However, a safe and effective strategy for delivery of an ASO to its targeted RNA remains as a major hurdle in translational advances. Human umbilical cord mesenchymal cell (hUC-MSC)-derived exosomes were used as vehicles to deliver an anti-miR-146b-5p ASO (PMO-146b). PMO-146b was assembled onto the surface of exosomes (e) through covalent conjugation to an anchor peptide CP05 (P) that recognized an exosomal surface marker, CD63, forming a complex named ePPMO-146b. After ePPMO-146b treatment, cell proliferation, uptake ability, and migration assays were performed, and epithelial-mesenchymal transition progression was evaluated in vitro. A mouse xenograft model was used to determine the antitumor effect and distribution of ePPMO-146b in vivo. ePPMO-146b was taken up by SW620 cells and effectively inhibited cell proliferation and migration. The conjugate also exerted antitumor efficacy in a xenograft mouse model of colon cancer by systematic administration, where PPMO-146b was enriched in tumor tissue. Our study highlights the potential of hUC-MSC-derived exosomes anchored with PPMO-146b as a novel safe and effective approach for PMO backboned ASO delivery.

IGH repertoire analysis at scale: deciphering the complexity of B cell infiltration and migration in esophageal squamous cell carcinoma.

Tumor-infiltrating B-lineage cells have become predictors of prognosis and immunotherapy responses in various cancers. However, limited knowledge about their infiltration and migration patterns has hindered the understanding of their anti-tumor functions. Here, we examined the immunoglobulin heavy chain (IGH) repertoires in 496 multi-regional tumor, 107 normal tissue, and 48 metastatic lymph node samples obtained from 107 patients with esophageal squamous cell carcinoma (ESCC). Our study revealed higher IgG-type B-lineage cells infiltration in tumors than in healthy tissue, which was associated with improved patient outcomes. Genes such as ACTN1, COL6A5, and pathways like focal adhesion, which shapes the physical structure of tumors, could affect B-lineage cell infiltration. Notably, the IGH sequence was used as an identity-tag to monitor B cell migration, and their infiltration schema within the tumor were depicted based on our multi-regional tumor specimens. This analysis revealed an escalation in B cell clones overlapped between metastatic lymph nodes and tumors. Therefore, the Lymph Node Activation Index was defined, which could predict the outcomes of patients with lymph node metastasis. This research introduces a novel framework for probing B cell infiltration and migration within the tumor microenvironment using large-scale transcriptome data, while simultaneously providing fresh perspectives on B cell immunology within ESCC.

Circ_0000370 Plays an Oncogenic Role in Colorectal Cancer by Regulating the miR-502-5p/SIRT1 Axis.

The importance of circular RNA has been reported in cancer development. However, the role and mechanism of circ_0000370 in CRC progression are still unclear. Quantitative real-time PCR and Western blot assay were performed to measure RNA and protein expression. Cell proliferation was assessed by cell colony formation assay and 5-Ethynyl-2'-deoxyuridine assay. Flow cytometry was used to measure cell apoptosis. Cell migration and invasion were detected by transwell assay. The intermolecular target relations between miR-502-5p and circ_0000370 or SIRT1 were confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. A xenograft tumor model was established to examine the role of circ_0000370 in tumor growth in vivo. As compared with controls, the expression of circ_0000370 was upregulated in CRC tissues and cells. Circ_0000370 depletion inhibited CRC cell proliferation, migration and invasion but induced cell apoptosis. Meanwhile, circ_0000370 depletion restrained tumor growth in vivo. In addition, miR-502-5p inhibitor partly reverted the impacts of circ_0000370 knockdown on CRC cells. Moreover, miR-502-5p mimic-caused effects on cell phenotypes were attenuated by SIRT1 overexpression. Circ_0000370 induced the proliferation and metastasis of CRC cells by sponging miR-502-5p and enhancing SIRT1 expression, which provided a possible target for CRC treatment.

SOX8 promotes tumor growth and metastasis through FZD6-dependent Wnt/ß-catenin signaling in colorectal carcinoma.

SOX8 plays an important role in several physiological processes. Its expression is negatively associated with overall survival in patients with colorectal carcinoma (CRC), suggesting SOX8 is a potential prognostic factor for this disease. However, the role of SOX8 in CRC remains largely unknown. In this study, our data showed that SOX8 expression was upregulated in CRC cell lines and tumor tissues. Stable knockdown of SOX8 in CRC cell lines dramatically reduced cell proliferation, migration, and invasion. Furthermore, the knockdown of SOX8 decreased the phospho-GSK3ß level and suppressed Frizzled-6 (FZD6) transcription; restoration of FZD6 expression partially abolished the effect of SOX8 on Wnt/ß-catenin signaling and promote CRC cell proliferation. In conclusion, our findings suggested that SOX8 served as an oncogene in CRC through the activation of FZD6-dependent Wnt/ß-catenin signaling.

Promising preclinical patient-derived organoid (PDO) and xenograft (PDX) models in upper gastrointestinal cancers: progress and challenges.

Gastrointestinal (GI) cancers (gastric cancer, oesophageal cancer, liver cancer, colorectal cancer, etc.) are the most common cancers with the highest morbidity and mortality in the world. The therapy for most GI cancers is difficult and is associated with a poor prognosis. In China, upper GI cancers, mainly gastric cancer (GC) and oesophageal cancer (EC), are very common due to Chinese people's characteristics, and more than half of patients are diagnosed with distant metastatic or locally advanced disease. Compared to other solid cancers, such as lung cancer and breast cancer, personalized therapies, especially targeted therapy and immunotherapy, in GC and EC are relatively lacking, leading to poor prognosis. For a long time, most studies were carried out by using in vitro cancer cell lines or in vivo cell line-derived xenograft models, which are unable to reproduce the characteristics of tumours derived from patients, leading to the possible misguidance of subsequent clinical validation. The patient-derived models represented by patient-derived organoid (PDO) and xenograft (PDX) models, known for their high preservation of patient tumour features, have emerged as a very popular platform that has been widely used in numerous studies, especially in the research and development of antitumour drugs and personalized medicine. Herein, based on some of the available published literature, we review the research and application status of PDO and PDX models in GC and EC, as well as detail their future challenges and prospects, to promote their use in basic and translational studies or personalized therapy.

IL23R as an indicator of immune infiltration and poor prognosis in intrahepatic cholangiocarcinoma: a bioinformatics analysis.

Background: Although the incidence of intrahepatic cholangiocarcinoma (CHOL) is low, the prognosis is very poor. The expression level of interleukin 23 receptor (IL23R) is linked to the occurrence and development of cancers. This study aimed to identify the role of IL23R in CHOL using bioinformatics tools and experimental validation. Methods: Circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) datasets were obtained from the Gene Expression Omnibus (GEO) database, and R software was used for data analysis and visualization. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to conduct functional enrichment analysis, which was verified with gene set enrichment analysis software. Clinical data were obtained from The Cancer Genome Atlas (TCGA), and survival analyses were performed using the DriverDBv3 database and the Gene Expression Profiling Interactive Analysis website. The TIMER2.0 database provided us for immune cell infiltration analysis results of IL23R. Real-time quantitative polymerase chain reaction (RT-qPCR) was used for IL23R expression verification. Results: Differentially expressed (DE) mRNAs were enriched in phosphoinositide 3-kinase-serine/threonine kinase signaling pathway, immune-related tumor microenvironment (TME), and amino acid metabolism, etc. In addition, expression of IL23R was associated with immune infiltration-related cells. Furthermore, a circRNA-miRNA-IL23R network and a IL23R protein-protein interaction network were established. Most importantly, IL23R, as a prognostic gene, was found to have a low expression in CHOL. Conclusions: A circRNA-miRNA-IL23R network was identified, and it was found that IL23R may be a prognostic and immune-related biomarker in CHOL, which is worthy of further exploration.

Immune activity score to assess the prognosis, immunotherapy and chemotherapy response in gastric cancer and experimental validation.

Background: Gastric cancer (GC) is an extremely heterogeneous malignancy with a complex tumor microenvironment (TME) that contributes to unsatisfactory prognosis. Methods: The overall activity score for assessing the immune activity of GC patients was developed based on cancer immune cycle activity index in the Tracking Tumor Immunophenotype (TIP). Genes potentially affected by the overall activity score were screened using weighted gene co-expression network analysis (WGCNA). Based on the expression profile data of GC in The Cancer Genome Atlas (TCGA) database, COX analysis was applied to create an immune activity score (IAS). Differences in TME activity in the IAS groups were analyzed. We also evaluated the value of IAS in estimating immunotherapy and chemotherapy response based on immunotherapy cohort. Gene expression in IAS model and cell viability were determined by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and Cell Counting Kit-8 (CCK-8) assay, respectively. Results: WGCAN analysis screened 629 overall activity score-related genes, which were mainly associated with T cell response and B cell response. COX analysis identified AKAP5, CTLA4, LRRC8C, AOAH-IT1, NPC2, RGS1 and SLC2A3 as critical genes affecting the prognosis of GC, based on which the IAS was developed. Further RT-qPCR analysis data showed that the expression of AKAP5 and CTLA4 was downregulated, while that of LRRC8C, AOAH-IT1, NPC2, RGS1 and SLC2A3 was significantly elevated in GC cell lines. Inhibition of AKAP5 increased cell viability but siAOAH-IT1 promoted viability of GC cells. IAS demonstrated excellent robustness in predicting immunotherapy outcome and GC prognosis, with low-IAS patients having better prognosis and immunotherapy. In addition, resistance to Erlotinib, Rapamycin, MG-132, Cyclopamine, AZ628, and Sorafenib was reduced in patients with low IAS. Conclusion: IAS was a reliable prognostic indicator. For GC patients, IAS showed excellent robustness in predicting GC prognosis, immune activity status, immunotherapy response, and chemotherapeutic drug resistance. Our study provided novel insights into the prognostic assessment in GC.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Stereotactic ablative radiotherapy and FAPα-based cancer vaccine suppresses metastatic tumor growth in 4T1 mouse breast cancer.

BACKGROUND AND PURPOSE: This study tested the hypothesis that a novel combination of stereotactic ablation radiotherapy (SABR) and a cancer vaccine against fibroblast activation protein-alpha (FAPα) can suppress established tumor growth and impede potential metastasis. METHODS: The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were randomly assigned to five treatment groups: (1) untreated control, (2) FAPα-based cancer vaccine, (3) SABR, (4) SABR + pCDH (lentiviral control vector), (5) SABR + FAPα-based cancer vaccine (SABR/FAPα-Vax). FAPα-based cancer vaccine were administered subcutaneously every week for a total of three treatments. SABR was delivered to the primary tumor by 3 × 8 Gy after the first vaccination. RESULTS: Consistent with the poorly immunogenic nature of 4T1, tumor-bearing mice receiving FAPα-based cancer vaccine or SABR monotherapy showed a modest reduction in tumor volume and increased animal lifespan. In contrast, SABR/FAPα-Vax was well-tolerated, significantly reduced tumor burden, and increased survival compared to monotherapy. The increased survival correlated with inhibition of extracellular matrix (ECM) production, tumor vascularization and lymphangiogenesis. SABR/FAPα-Vax also resulted in an abscopal effect capable of eliminating lung metastases. SABR/FAPα-Vax recruited and activated CD8 + T cells to attack tumor cells and FAPα + stromal cells, and initiated suppressor cell reprogramming, including facilitating macrophage polarization toward an anti-tumor (M1) state, as well as depleting myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). CONCLUSION: These findings provide a novel therapeutic combination of radiation and FAPα-based cancer vaccine with promising results against poorly immunogenic metastatic cancer. This study may pave the way to overcome the therapeutic resistance caused by FAPα + CAFs.