OBJECTIVE:The main objective of this study is to investigate the prognostic value of serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) in predicting postoperative outcomes for hepatocellular carcinoma (HCC) patients after surgical resection. METHODS:Serum PIVKA‑II levels were compared between early‑stage (stage I+II) and advanced‑stage (stage III+IV) HCC patients. Correlations between PIVKA‑II and clinicopathological features were examined. Kaplan‑Meier curves were plotted to assess overall survival (OS) and recurrence‑free survival (RFS) by PIVKA‑II levels. Receiver operating characteristic (ROC) analysis compared the predictive performance of PIVKA‑II and α ‑fetoprotein (AFP), with DeLong 's test evaluating differences in area under the curve. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors for postoperative survival and recurrence. RESULTS:Serum PIVKA‑II levels were significantly elevated in HCC patients compared with controls ( P < 0.01), and were higher in advanced‑stage than early‑stage HCC ( P < 0.01). PIVKA‑II correlated significantly with tumor diameter, tumor node metastasis classification, lymph node infiltration, distant metastasis, differentiation, and complication incidence (all P < 0.05). Patients with high PIVKA‑II (≥100 mAU/ml) had shorter median OS and RFS than those with low levels (<100 mAU/ml) ( P < 0.01). PIVKA‑II outperformed AFP in predicting 5‑year survival and recurrence ( P < 0.05), and combined use improved predictive accuracy ( P < 0.05). Multivariate Cox regression identified PIVKA‑II ≥100 mAU/ml as an independent prognostic factor for both OS and RFS ( P < 0.05). CONCLUSION:Our study confirms that serum PIVKA-II can serve as a prognostic predictor for HCC patients after surgical treatment.

The ATP synthase-associated macromolecular complex plays a crucial role in cellular energy homeostasis. However, the regulation and potential function of this complex remain poorly understood in cancer. Here, we identify a 170-amino acid protein encoded by the lncRNA LINC00528, which we term ATP synthase-associated macromolecular complex enhancing microprotein (ATHENA). Mechanistically, ATHENA localizes to the mitochondrial inner membrane, in which ATHENA directly interacts with ATP synthase subunits (β and γ) and solute carrier proteins, including ANT and PiC, thereby promoting the assembly of these macromolecular complexes, enhancing ATP synthesis, and preserving mitochondrial and cristae architecture. Functionally, ATHENA promotes the proliferation, migration, and invasion of renal cell carcinoma (RCC) cells in vitro and drives RCC tumor growth and metastasis in vivo. Clinically, ATHENA is upregulated in RCC tissues and associated with poorer prognosis in RCC patients. Collectively, our findings identify ATHENA as a previously unrecognized mitochondrial microprotein that facilitates the assembly of ATP synthase-associated macromolecular complex and drives RCC progression.

Background and PurposeInvestigating the assessment of innovative serum indicators with elevated sensitivity and specificity is crucial for enhancing the early diagnosis and prognosis of HCC (Hepatocellular carcinoma). This study aimed to evaluate the efficacy of COPA (Coatomer Subunit Alpha) in diagnosing hepatocellular carcinoma and assessing the effectiveness of immunotherapy.MethodsThis study included two cohorts: a diagnostic cohort comprising 81 healthy controls, 118 patients with benign liver diseases, and 81 patients with pathologically confirmed HCC, and an immunotherapy cohort comprising 131 HCC patients treated with PD-1/PD-L1 inhibitors. Serum COPA was measured by ELISA, while AFP and PIVKA-II were measured by electrochemiluminescence. Diagnostic performance and immunotherapy monitoring efficacy were then evaluated.ResultsCOPA is upregulated in serum and HCC tumor samples. The ROC analysis indicated that the diagnostic efficacy of COPA (AUC = 0.911) surpassed that of traditional biomarkers. Importantly, COPA retained favorable diagnostic performance in both AFP-negative and PIVKA-II-negative HCC patients. Dynamic monitoring revealed that when comparing PIVKAII and AFP with imaging-based efficacy assessments, serum COPA changes demonstrated superior consistency pre- and post-immunotherapy (Kappa of COPA = 0.73, P < 0.01). COPA expression was significantly elevated in HCC tissues compared with adjacent non-tumor tissues.ConclusionThis study established that COPA outperforms AFP and PIVKAII in diagnostic and immunotherapeutic monitoring reliability, offering a novel technique for the precise diagnosis and treatment of hepatocellular carcinoma.

Human epidermal growth factor receptor 2 (HER2) is a critical biomarker for targeted therapy of gastric cancer. Tissue-based HER2 testing via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) remains the clinical gold standard, while serum HER2 represents a potential complementary circulating biomarker for disease monitoring. However, conventional serum HER2 assays often suffer from limited sensitivity. Herein, we develop a highly sensitive fluorescence assay for serum HER2 detection using nonlinear hybridization chain reaction (NHCR) coupled with a HER2-specific aptamer (HB5). Unlike linear hybridization chain reaction (HCR), NHCR enables branching-mediated exponential amplification, in which each trigger initiates multiple independent HCR cascades, leading to nonlinear signal growth. The method exhibited a good linear relationship (R 2 = 0.993) in the HER2 concentration range of 0.5-90 ng·mL-1, with a detection limit as low as 38 pg·mL-1. The sensor demonstrated excellent specificity for HER2, good reproducibility, and reliable stability. Clinical serum sample detection results indicated that the method was highly correlated with the clinically commonly used chemiluminescence immunoassay (CLIA), with spiked recoveries ranging from 95.4% to 109.6%. The NHCR-based fluorescent detection strategy established in this study provides a new tool for accurate and noninvasive detection of serum HER2, featuring simple operation and controllable cost.

The immunoregulatory cytokine interleukin (IL)-35 has been implicated in the pathogenesis of hepatocellular carcinoma (HCC). Here, we explored the association between single-nucleotide polymorphisms (SNPs) in the IL-35 gene and the occurrence of HCC in patients with chronic hepatitis B virus (HBV). We selected 39 patients with chronic hepatitis B (HBV) and 52 patients with HBV-related hepatocellular carcinoma (HCC) as the case groups, along with 42 healthy individuals as the control group. We genotyped five IL-35-related single-nucleotide polymorphisms (SNPs) and analyzed their association with HCC risk. In addition, serum IL-35 levels, lymphocyte counts, and regulatory T cell (Treg) frequencies were measured in peripheral blood across all groups. The frequency of the rs583911 AA genotype tended to increase from healthy controls (4.8

Early and accurate detection of multiple cancers through a single test remains an unmet clinical need, hindered by current limitations in accuracy, throughput, automation, and multiplexing. Here, we present an AI-powered SERS chip that combines automated exosome capture with AI-enabled molecular fingerprinting to accurately distinguish ten common cancer types from a single serum test. The system employs a peptide-functionalized SERS chip enabling the selective enrichment of exosomes directly from patient serum, enhancing label-free Raman fingerprint signals. AI-driven spectral analysis achieved 97.4% accuracy in distinguishing cancer from healthy samples, 97.08% accuracy for early-stage cancer detection, and 93.89% accuracy in classifying ten common cancer types, including breast, thyroid, esophageal, kidney, pancreatic, duodenal, lung, colorectal, ovarian, and gastric cancers. Crucially, based on molecular profiling, we identified exosomal deoxyadenosine triphosphate as a promising pan-cancer biomarker consistently upregulated across diverse tumor types. This discovery establishes a potential pan-cancer diagnostic marker, while the fully automated, scalable platform offers significant promise for clinical translation in early and differential cancer diagnosis.

Background:An elevated peripheral blood neutrophil-to-lymphocyte ratio (NLR) has been reported to be a negative prognostic marker in many types of cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether NLR is associated with the tumor-immune microenvironment (TIME) in PDAC is unclear. Understanding the interplay between systemic inflammation as reflected by NLR and TIME in PDAC is crucial for identifying prognostic biomarkers and potential therapeutic targets. The aim of this study was to examine the relationship between the NLR and clinical outcomes in patients with early-stage PDAC and the impact of the TIME in PDAC. Methods:We conducted a retrospective analysis including two cohorts: PDAC patients versus healthy controls and untreated stage I-II PDAC cases. We collected clinical data, including NLR values and followed PDAC patients for overall survival (OS) and relapse-free survival (RFS), and the TIME was evaluated through immunohistochemical staining for CD8+ T cells and CD33+ myeloid-derived suppressor cells (MDSCs). Statistical analyses were performed to assess the relationship between NLR, clinical outcomes, and TIME components to further determine the value of NLR in reflecting the status of the TIME and predicting outcomes of patients with PDAC. Results:NLR was negatively associated with OS and RFS in patients with PDAC. Moreover, NLR was found to be a prognostic factor for PDAC and early-stage PDAC. The NLR was inversely correlated with the abundance of tumoral CD8+ T cells (r=-0.345, P=0.004) and positively correlated with that of CD33+ MDSCs (r=0.407, P=0.001). Conclusions:Our findings indicate that a high NLR value is closely correlated with poor outcomes in patients with PDAC. In addition, it was significantly associated with the presence of tumoral CD8+ tumor-infiltrating lymphocytes and CD33+ cells in the TIME of patients with PDAC. NLR may be a biomarker that can inform treat-related decision-making.

Focused ultrasound ablation surgery (FUAS), a minimally invasive therapeutic strategy, has demonstrated potential in breast cancer treatment but is limited by incomplete tumor irradiation and the damage to normal tissues. Here, we present a novel platform utilizing mesoporous silica nanoparticles (MSNs), functionalized with polyethylene glycol (PEG) and polyethyleneimine (PEI), encapsulating astragaloside IV (AS) and gated with 1-tetradecanol (TD). These NPs (PP@M-TD/AS) attach to Bifidobacterium bifidum (BF) via electrostatic adsorption. Leveraging BF's tumor-targeting ability in hypoxic microenvironments, the NPs enable specific accumulation in tumor site, facilitating targeted and efficient drug delivery. FUAS-induced thermal effects trigger the phase transition of TD, facilitating on-demand AS release at the tumor site. This approach enhances FUAS-mediated tumor ablation by improving acoustic impedance and ensuring precise drug delivery, leading to significant tumor suppression. Moreover, the system exhibited extended retention at the tumor site and excellent biocompatibility with minimal systemic toxicity. This platform effectively addresses the limitations of FUAS, offering a highly efficient and targeted approach for advancing breast cancer therapy.

SERPINI1 is a protein-coding gene, which has been reported to be related to malignancies, and the encoding protein is a secreted protein. Nevertheless, the specific effect of SERPINI1 on Hepatocellular carcinoma (HCC) remains unclear. The expression level of SERPINI1 in cancers was detected by the Gene Expression Omnibus (GEO) database, the Gene Expression Profiling Interactive Analysis (GEPIA) database and the collected serum of HCC patients. The receiver operating characteristic (ROC) curve and area under curve (AUC) were used to evaluate the diagnostic effectiveness of serum SERPINI1 and the combination of AFP and SERPINI1 for HCC. The Kaplan-Meier (KM) survival was used to evaluate the prognostic capacity of SERPINI1 for HCC in GEPIA database. Furthermore, the correlations between clinicopathological characteristics and the level of serum SERPINI1 were analyzed. Besides, we detected the expression of SERPINI1 in HepG2 by qPCR and western blot, and confirmed the biological function of SERPINI1 through MTT, EdU, wound healing and transwell invasion assay. The results indicated that the level of SERPINI1 was significantly increased in tissue and serum of HCC patients. ROC analysis displayed that SERPINI1 had a significantly diagnostic value for HCC, the combination of AFP and SERPINI1 gained the higher specificity and sensitivity. The KM survival curves indicated that patients with SERPINI1 overexpression had worse overall survival. Furthermore, we found the positive correlations between serum SERPINI1 level and some clinicopathological characteristics, such as tumor size, differentiation degrees and so on. In addition, in vitro experiments revealed that SERPINI1 could promote the proliferation and invasion of HCC. Taken together, our study demonstrates that SERPINI1, which is highly expressed in HCC and closely related to cell proliferation and invasion, may serve as a novel biomarker for diagnosis and prognosis of HCC.

Correction for ‘Genetically engineered gas vesicle proteins with proliferative potential for synergistic targeted tumor therapy’ by Li Lin et al., RSC Adv., 2025, 15, 157–166, https://doi.org/10.1039/D4RA07532C.

Focused ultrasound ablation surgery (FUAS) combined with bacterial synergistic therapy has significant potential in solid tumors, however, this combination therapy has been limited mainly due to its weak anti-tumor effects, single imaging modality, and exhibition of tumor recurrence. Herein, we aim to develop a novel multifunctional bio-composite comprising the coating of polydopamine (pDA) and doxorubicin (DOX) on the surface of genetically engineered bacteria (GVs-E. coli) for the ultrasound imaging (USI) and photoacoustic imaging (PAI)-guided synergistic chemo-FUAS therapy of tumor. The bio-composite preferentially colonize into hypoxic tumor tissues, the gas vesicles (GVs) expressed in GVs-E. coli can effectively synergize to FUAS through their cavitation effect and perform USI, and the pDA coating on the surface can produce a uniform PAI signal. Simultaneously, FUAS can trigger the controlled release of chemotherapy drug DOX. Our results confirmed that a combination of biotherapy synergistic chemo-FUAS therapy resulted in significant tumor inhibition and extended survival of 4T1 breast tumor model. This strategy has the potential to solve the inherent limitations of traditional FUAS treatments, while improving the therapeutic effect in conjunction with chemotherapy. It provides a new paradigm for image-guided, multi-level collaborative anti-cancer therapy.

Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is a hallmark of cancer, yet the mechanisms driving aerobic glycolysis are unclear. In this study, we identified chromosome 19 open reading frame 12 (C19orf12), a gene associated with neurodegeneration, as upregulated in non-small cell lung cancer (NSCLC). Elevated C19orf12 expression is associated with poor prognosis and enhanced metastatic potential in NSCLC cells. High C19orf12 levels repress mitochondrial respiration and decrease glucose flux through the tricarboxylic acid cycle. Mechanistically, C19orf12 interacts with and suppresses the biological function of leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) and downregulates the expression of mitochondrial electron transport chain (ETC) genes. Moreover, C19orf12 increases NSCLC cell sensitivity to the tumoricidal effects of metformin by synergistically inhibiting mitochondrial respiration. These findings highlight C19orf12 as a regulator of mitochondrial metabolism in NSCLC and suggest that its elevated expression could serve as a biomarker to predict improved responses to metformin therapy.

Background:Lung cancer remains one of the leading causes of cancer-related deaths worldwide. Early detection is crucial for improving prognosis and survival rates. This study aimed to identify the low-abundance plasma proteins as potential diagnostic biomarkers for early-stage non-small cell lung cancer (NSCLC) and to distinguish malignant from benign lung nodules. Methods:Using a sodium-type Y zeolite-polymer polyanionic complex (NaY-PPC)-based low-abundance proteomics, we analyzed 181 plasma samples from healthy controls (HC; n=65), patients with benign lung nodules (BNs; n=21), and patients with early-stage NSCLC (n=95). Principal component analysis (PCA) and heatmap visualization were employed for differential analysis. The diagnostic performance of candidate biomarkers was evaluated using receiver operating characteristic (ROC) curves, and enzyme-linked immunosorbent assay (ELISA) was used for validation. Functional studies, including fructose-bisphosphate aldolase C (ALDOC) knockdown, were conducted to assess the role of ALDOC in NSCLC progression. Results:We identified 23 significantly differentially expressed proteins, with ALDOC showing the most promising diagnostic potential. ALDOC could effectively distinguish NSCLC patients from HCs [area under the curve (AUC) =0.994] and from those with BNs (AUC =0.720). Combining ALDOC with the traditional biomarkers carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin fragment 21-1 (CYFRA21-1) improved the differentiation between NSCLC and BN (AUC =0.824). ELISA validation confirmed the findings from the proteomics analysis. Additionally, ALDOC was upregulated in NSCLC tissues, and its high expression correlated with poor overall survival. Knockdown of ALDOC significantly reduced NSCLC cell growth and motility, suggesting its tumor-promoting role. Conclusions:ALDOC is a promising diagnostic biomarker for early-stage NSCLC, with potential clinical utility in distinguishing malignant lung nodules from BNs. This study highlights the value of low-abundance proteomics in identifying novel biomarkers for lung cancer detection and risk assessment.

β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently prevents Snail degradation by blocking recognition of E3 ubiquitin ligases FBXL14. Furthermore, either targeting Snail Kbhb modification or CBP inhibitor decreases cancer metastasis and enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells. Collectively, our study reveals that Kbhb of Snail is critical to promote metastasis and provides a potential therapeutic strategy.

The existence of cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) is considered to be the key factor for metastasis and chemoresistance. Thus, novel therapeutic strategies for eradicating CSCs are urgently needed. Here we aimed to explore the role of KLF15 in stemness and the feasibility of using KLF15 to inhibit CSCs and improve chemotherapy sensitivity in PDAC. In this study, we report that KLF15 is negatively associated with poor survival and advanced pathological staging of PDAC. Moreover, tumorous KLF15 suppresses the stemness of PDAC by promoting the degradation of Nanog, and KLF15 directly interacts with Nanog, inhibiting interaction between Nanog with USP21. We also demonstrate that the KLF15/Nanog complex inhibit the stemness in vivo and in PDX cells. Tazemetostat suppresses stemness and sensitizes PDAC cells to gemcitabine by promoting KLF15 expression in PDAC. In summary, the findings of our study confirm the value of KLF15 level in diagnosis and prognosis of PDAC, it is the first time to explore the inhibition role of KLF15 in stemness of PDAC and the regulation mechanism of Nanog, contributing to provide a new therapeutic strategy that using Tazemetostat sensitizes PDAC cells to gemcitabine by promoting KLF15 expression for PDAC.

OBJECTIVES:China, which has the largest number of patients with primary liver cancer (PLCs), lacks data on the overall prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in PLCs. We aimed to comprehensively assess the seroprevalence of HBV and HCV among PLCs in China. METHODS:We included and pooled observational studies reporting seroprevalence of HBsAg and anti-HCV antibodies among PLCs in China by searching PubMed, Web of Science, Cochrane, Scopus, Embase, CNKI, Wanfang, and CBM. Multivariate meta-regression and subgroup analyses were used to explore sources of heterogeneity, and publication bias was assessed by funnel plots and Egger's test. PROSPERO registration number is CRD42023450382. RESULTS:A total of 217 eligible studies were included in the meta-analysis. The estimated seroprevalence of HBV and HCV in PLCs was 75.09% (95% CI 73.12-77.02) and 11.82% (95% CI 9.79-14.00), respectively. After stratifying and analysing subgroups by region and study period, we found geographic differences in HBV and HCV prevalence among PLCs, with an overall increasing trend in the proportion of HBV and a decreasing trend in the proportion of HCV as well as co-infections in the last 40 years. CONCLUSIONS:HBV and HCV infections still account for a high proportion of PLCs in China.

Background Noninvasive biomarkers for the assessment of response to chemotherapy in advanced breast cancer (BCa) are essential for optimized therapeutic decision-making. We evaluated the potential of soluble Periostin (POSTN) in circulation as a novel biomarker for chemotherapy efficacy monitoring. Methods Two hundred and thirty-one patients with different stages of BCa were included. Of those patients, 58 patients with inoperable metastatic disease receiving HER2-targeted or non-targeted chemotherapy were enrolled to assess the performances of markers in recapitulating the chemotherapy efficacy assessed by imaging. POSTN, together with CA153 or CEA at different time points (C0, C2, and C4) were determined. Results POSTN levels were significantly associated with tumor volume ( P < 0.0001) and TNM stages ( P < 0.0001) of BCa. For early monitoring, dynamics of POSTN could recapitulate the chemotherapy efficacy among all molecular subtypes (Cohen’s weighted kappa = 0.638, P < 0.0001), much better than that of carcinoembryonic antigen (CEA) and cancer antigen 153 (CA15-3). For early partial response, superior performance of POSTN was observed (Cohen’s weighted kappa = 0.827, P < 0.0001) in cases with baseline levels above 17.19 ng/mL. For long-term monitoring, the POSTN response was observed to be strongly consistent with the course of the disease. Moreover, progression free survival analysis showed that patients experienced a significant early decrease of POSTN tended to obtain more benefits from the treatments. Conclusions The current study suggests that soluble POSTN is an informative serum biomarker to complement the current clinical approaches for early and long-term chemotherapy efficacy monitoring in advanced BCa.

This study aimed to establish a novel noninvasive model based on the serum N-glycan spectrum for providing an objective value for determining the stage of liver necroinflammation related to chronic hepatitis B (CHB) patients. N-glycan profiles of the sera of 295 treatment-naïve CHB patients were analyzed. N-glycan profiles were tested for different liver necroinflammation stages using DNA sequence-assisted fluorophore-assisted carbohydrate electrophoresis. A serum N-glycan model named N-glycan-LI (NGLI) using support vector machine was selected to evaluate the classification of liver necroinflammation (G < 2 and G ≥ 2). The area under the receiver operating characteristic curves (AUROCs) was 0.898 (training set, n = 236) and 0.911 (validation set, n = 59) regardless of the stage of liver fibrosis (AUROC = 0.886 and 0.926, respectively, in S < 2 and S ≥ 2 group). The NGLI correspondingly had the highest specificity (SP) of 90.79% and negative predictive value of 92.00% in an inactive stage (including immune-tolerant [IT] and inactive-carrier [IC] stage), had the highest positive predictive value of 95.18% in stage immune-active, and had the highest SP of 93.94% in grey zone IT + IC. N-glycan profiles appear to correlate well with hepatic necroinflammation in CHB when compared with liver biopsy. The newly developed model appears to reliably predict liver damage in naïve-treatment patients with CHB.

Background:Solute carrier family 16 member 1 (SLC16A1) serves as a biomarker in numerous types of cancer. Tumor immune infiltration has drawn increasing attention in cancer progression and treatment. The objective of our study was to explore the association between SLC16A1 and the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC).Methods:Data were obtained from The Cancer Genome Atlas. The xCell web tool was used to calculate the proportion of immune cells according to SLC16A1 expression. To further explore the mechanism of SLC16A1, immunity-related genes were screened from differentially expressed genes through weighted gene coexpression network analysis, examined via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, and filtrated using univariate Cox regression and least absolute shrinkage and selection operator regression model combined correlation analysis (P<0.05). Next, CIBERSORT was used to analyze the correlation between immune cells and five important genes. SLC16A1 expression and its clinical role in pancreatic cancer was clarified via immunohistochemical staining experiments. Finally, the effects of SLC16A1 on the results of cancer immunity were evaluated by in vitro experiments.Results:SLC16A1 was overexpressed in PDAC tissues and could be an independent prognostic factor. SLC16A1 was significantly negatively correlated with overall survival and suppressed the tumor immunity of PDAC. In clinic, SLC16A1 expression was significantly positively correlated with tumor progression and poor prognosis. We also found that SLC16A1 could suppress the antitumor ability of CD8+ T cells.Conclusions:SLC16A1 is a biomarker for the prognosis of PDAC and can influence the immune environment of PDAC. These findings provide new insights into the treatment of PDAC.