The landscape of etiological patterns of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in Thailand.

Thailand is among countries with the highest global incidence and mortality rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). While viral hepatitis and liver fluke infections have been associated with HCC and iCCA, respectively, other environmental risk factors, overall risk factor commonality and combinatorial roles, and effects on survival have not been systematically examined. We conducted a TIGER-LC consortium-based population study covering all high-incidence areas of both malignancies across Thailand: 837 HCC, 1474 iCCA, and 1112 controls (2011-2019) were comprehensively queried on lifelong environmental exposures, lifestyle, and medical history. Multivariate logistic regression and Cox proportional hazards analyses were used to evaluate risk factors and associated survival patterns. Our models identified shared risk factors between HCC and iCCA, such as viral hepatitis infection, liver fluke infection, and diabetes, including novel and shared associations of agricultural pesticide exposure (OR range of 1.50; 95% CI: 1.06-2.11 to 2.91; 95% CI: 1.82-4.63) along with vulnerable sources of drinking water. Most patients had multiple risk factors, magnifying their risk considerably. Patients with lower risk levels had better survival in both HCC (HR 0.78; 95% CI: 0.64-0.96) and iCCA (HR 0.84; 95% CI: 0.70-0.99). Risk factor co-exposures and their common associations with HCC and iCCA in Thailand emphasize the importance for future prevention and control measures, especially in its large agricultural sector. The observed mortality patterns suggest ways to stratify patients for anticipated survivorship and develop plans to support medical care of longer-term survivors, including behavioral changes to reduce exposures.

Norcantharidin Enhances the Antitumor Effect of 5-Fluorouracil by Inducing Apoptosis of Cervical Cancer Cells: Network Pharmacology, Molecular Docking, and Experimental Validation.

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.

Plexin domain-containing 1 may be a biomarker of poor prognosis in hepatocellular carcinoma patients, may mediate immune evasion.

BACKGROUND: For the first time, we investigated the oncological role of plexin domain-containing 1 (PLXDC1), also known as tumor endothelial marker 7 (TEM7), in hepatocellular carcinoma (HCC). AIM: To investigate the oncological profile of PLXDC1 in HCC. METHODS: Based on The Cancer Genome Atlas database, we analyzed the expression of PLXDC1 in HCC. Using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting, we validated our results. The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features, such as patient survival, methylation level, tumor immune microenvironment features, and immune cell surface checkpoint expression. Finally, to assess the immune evasion potential of PLXDC1 in HCC, we used the tumor immune dysfunction and exclusion (TIDE) website and immunohistochemical staining assays. RESULTS: Based on immunohistochemistry, qRT-PCR, and Western blot assays, overexpression of PLXDC1 in HCC was associated with poor prognosis. Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor. In HCC patients with high methylation levels, the prognosis was worse than in patients with low methylation levels. Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling, and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup. The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis, and PLXDC1-related risk scores were also associated with a poor prognosis. CONCLUSION: As a result of this study analyzing PLXDC1 from multiple biological perspectives, it was revealed that it is a biomarker of poor prognosis for HCC patients, and that it plays a role in determining immune evasion status.

Single-cell analysis of a progressive Rosai-Dorfman disease affecting the cerebral parenchyma: a case report.

Neurologic Rosai-Dorfman disease (RDD) is a rare type of non-Langerhans cell histiocytosis that affects the central nervous system. Most neurologic RDDs grow like meningiomas, have clear boundaries, and can be completely resected. However, a few RDDs are invasive and aggressive, and no effective treatment options are available because the molecular mechanisms involved remain unknown. Here, we report a case of deadly and glucocorticoid-resistant neurologic RDD and explore its possible pathogenic mechanisms via single-cell RNA sequencing. First, we identified two distinct but evolutionarily related histiocyte subpopulations (the C1Q+ and SPP1+ histiocytes) that accumulated in the biopsy sample. The expression of genes in the KRAS signaling pathway was upregulated, indicating gain-of-function of KRAS mutations. The C1Q+ and SPP1+ histiocytes were highly differentiated and arrested in the G1 phase, excluding the idea that RDD is a lympho-histio-proliferative disorder. Second, although C1Q+ histiocytes were the primary RDD cell type, SPP1+ histiocytes highly expressed several severe inflammation-related and invasive factors, such as WNT5A, IL-6, and MMP12, suggesting that SPP1+ histiocytes plays a central role in driving the progression of this disease. Third, oligodendrocytes were found to be the prominent cell type that initiates RDD via MIF and may resist glucocorticoid treatment via the MDK and PTN signaling pathways. In summary, in this case, we report a rare presentation of neurologic RDD and provided new insight into the pathogenic mechanisms of progressive neurologic RDD. This study will also offer evidence for developing precision therapies targeting this complex disease.

HIF-1α facilitates glioma proliferation and invasion by activating pyroptosis signaling axis.

BACKGROUND: HIF-1α is thought to be a novel regulator which contributes to carcinogenesis. However, the mechanism underlying the effect of HIF-1α in gliomas remains largely unknown. METHODS: In the research, we demonstrate that HIF-lα mRNA and protein levels are elevated in glioma cells. The colony formation assays, transwell assays, and wound-healing assays showed that overexpression of HIF-1α promoted proliferation and invasion of glioma cells. RESULTS: Overexpression of HIF-lα also increased the expression of inflammatory factors related to pyrolysis (TNF-α, IL-10, and IL-1ß) and protein related to pyrolysis signal pathway (NLRP3, ASC, caspase-1, GSDMD, and GSDME). CONCLUSIONS: Therefore, we speculate that HIF-1α promotes the proliferation and invasion of glial cells by regulating pyrolysis pathway. These results might provide a novel strategy and target for treatment of glioma.

Associations between postoperative cognitive dysfunction, serum interleukin-6 and postoperative delirium among patients after coronary artery bypass grafting: A mediation analysis.

BACKGROUND: POCD is a common complication among patients who underwent coronary artery bypass graft (CABG), it is linked to loss of independence and reduced quality of life. AIMS AND OBJECTIVES: To examine the association between postoperative cognitive dysfunction (POCD), postoperative delirium (POD) and interleukin-6 (IL-6). DESIGN: A prospective cohort study. METHODS: Patients who underwent elective isolated CABG were enrolled. POCD was assessed by a set of cognitive function tools. Delirium was assessed using the CAM-ICU. The logistic regression analyses were used to identify the predictive value of POD or IL-6 on POCD. The path analysis was used to analyse the relationship among POD, IL-6 and POCD. RESULTS: A total of 212 patients were enrolled, with 25.0% of patients developing POD and 32.5% developing POCD. The multiple logistic regression analysis revealed that patients with POD had a four-fold increased hazard of POCD (OR = 3.655), and patients with IL-6 ≥ 830.50 pg/mL at the 6th hours after surgery had a 5-fold increased risk of experiencing POCD (OR = 5.042). However, the mediation effect of POD between IL-6 and POCD was not statistically significant (ß = 0.059, p = .392). CONCLUSIONS: POD and IL-6 at the 6th hour after surgery (≥830.50 pg/mL) are two potent predictors for POCD, while POD did not play a mediation effect between IL-6 and POCD. RELEVANCE TO CLINICAL PRACTICE: Early identification of risk factors (e.g., delirium assessment and testing for serum IL-6 levels) by clinical nurses for POCD may contribute to the clinical practice for the targeted prevention nursing strategies.

Eosinophil-activating Semiconducting Polymer Nanoparticles for Cancer Photo-immunotherapy.

Eosinophils are important immune effector cells that affect T cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the development of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe is composed of an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2-cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe can generate 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy.

Predictive potential of preoperative Naples prognostic score-based nomogram model for the prognosis in surgical resected thoracic esophageal squamous cell carcinoma patients: A retrospective cohort study.

The present study aimed to establish an effective prognostic nomogram model based on the Naples prognostic score (NPS) for resectable thoracic esophageal squamous cell carcinoma (ESCC). A total of 277 patients with ESCC, who underwent standard curative esophagectomy and designated as study cohort, were retrospectively analyzed. The patients were divided into different groups, including NPS 0, NPS 1, NPS 2, and NPS 3 or 4 groups, for further analysis, and the results were validated in an external cohort of 122 ESCC patients, who underwent surgery at another cancer center. In our multivariate analysis of the study cohort showed that the tumor-node-metastasis (TNM) stage, systemic inflammation score, and NPS were the independent prognostic factors for the overall survival (OS) and progression-free survival (PFS) durations. In addition, the differential grade was also an independent prognostic factor for the OS in the patients with ESCC after surgery (all P < .05). The area under the curve of receiver operator characteristics for the PFS and OS prediction with systemic inflammation score and NPS were 0.735 (95% confidence interval [CI] 0.676-0.795, P < .001) and 0.835 (95% CI 0.786-0.884, P < .001), and 0.734 (95% CI 0.675-0.793, P < .001) and 0.851 (95% CI 0.805-0.896, P < .001), respectively. The above independent predictors for OS or PFS were all selected in the nomogram model. The concordance indices (C-indices) of the nomogram models for predicting OS and PFS were 0.718 (95% CI 0.681-0.755) and 0.669 (95% CI 0.633-0.705), respectively, which were higher than that of the 7th edition of American Joint Committee on Cancer TNM staging system [C-index 0.598 (95% CI 0.558-0.638) for OS and 0.586 (95% CI 0.546-0.626) for PFS]. The calibration curves for predicting the 5-year OS or PFS showed a good agreement between the prediction by nomogram and actual observation. In the external validation cohort, the nomogram discrimination for OS was better than that of the 7th edition of TNM staging systems [C-index: 0.697 (95% CI 0.639-0.755) vs 0.644 (95% CI 0.589-0.699)]. The calibration curves showed good consistency in predicting the 5-year survival between the actual observation and nomogram predictions. The decision curve also showed a higher potential of the clinical application of predicting the 5-years OS of the proposed nomogram model as compared to that of the 7th edition of TNM staging systems. The preoperative NPS-based nomogram model had a certain potential role for predicting the prognosis of ESCC patients.

Alcohol-associated liver cancer.

Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated HCC (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop post alcohol-associated cirrhosis, but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of pre-clinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis are also discussed.

Curcumin activates the JNK signaling pathway to promote ferroptosis in colon cancer cells.

Recent evidence has proved that curcumin as a natural polyphenol have a great anticancer and anti-proliferative effects in cancer cells. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. In this study, we aimed to examine the effects of curcumin in ferroptosis of human colorectal cancer cells and its underlying molecular mechanisms. SW-480 colorectal cancer cells were treated by curcumin with different concentrations. Cell viability was determined by using MTT assay. The concentrations of reactive oxygen species (ROS) and intracellular iron were measured using specific related kits. Real-time PCR and Western blot analysis were used to determine the expression of ferroptosis-related proteins including ACSL4, GPx4 and FTH1 and activation of JNK protein. Curcumin suppressed SW-480 cancer cells viability in dose-dependent manner. Cell treatment with curcumin led to accumulation of ROS and iron within cells and increase in the intracellular levels of lipid peroxidation. In addition, curcumin modulated the mRNA and protein expression levels of ferroptosis-related proteins including ACSL4, GPx4 and FTH1 and suppression of JNK signaling. Curcumin may exhibit its anticancer effect on colorectal cancer by downregulating JNK signaling to induce ferroptosis in SW-480 cells.

Xiashengella succiniciproducens gen. nov., sp. nov., a succinate-producing bacterium isolated from an anaerobic digestion tank in the family Marinilabiliaceae of the order Bacteroidales.

A strictly anaerobic, motile bacterium, designated as strain Ai-910T, was isolated from the sludge of an anaerobic digestion tank in China. Cells were Gram-stain-negative rods. Optimal growth was observed at 38 °C (growth range 25-42 °C), pH 8.5 (growth range 5.5-10.5), and under a NaCl concentration of 0.06% (w/v) (range 0-2.0%). Major cellular fatty acids were iso-C15 : 0 and anteiso-C15 : 0. The respiratory quinone was MK-7. Using xylose as the growth substrate, succinate was produced as the fermentation product. Phylogenetic analysis based on the 16 S rRNA gene sequences indicated that strain Ai-910T formed a distinct phylogenetic lineage that reflects a new genus in the family Marinilabiliaceae, sharing high similarities to Alkaliflexus imshenetskii Z-7010T (92.78%), Alkalitalea saponilacus SC/BZ-SP2T (92.51%), and Geofilum rubicundum JAM-BA0501T (92.36%). Genomic similarity (average nucleotide identity and digital DNA-DNA hybridization) values between strain Ai-910T and its phylogenetic neighbors were below 65.27 and 16.90%, respectively, indicating that strain Ai-910T represented a novel species. The average amino acid identity between strain Ai-910T and other related members of the family Marinilabiliaceae were below 69.41%, supporting that strain Ai-910T was a member of a new genus within the family Marinilabiliaceae. Phylogenetic, genomic, and phenotypic analysis revealed that strain Ai-910T was distinguished from other phylogenetic relatives within the family Marinilabiliaceae. The genome size was 3.10 Mbp, and the DNA G + C content of the isolate was 42.8 mol%. Collectively, differences of the phenotypic and phylogenetic features of strain Ai-910T from its close relatives suggest that strain Ai-910T represented a novel species in a new genus of the family Marinilabiliaceae, for which the name Xiashengella succiniciproducens gen. nov., sp. nov. was proposed. The type strain of Xiashengella succiniciproducens is Ai-910T (= CGMCC 1.17893T = KCTC 25,304T).

Diagnostic Value of GDF10 for the Tumorigenesis and Immune Infiltration in Lung Squamous Cell Carcinoma.

OBJECTIVE: Lung squamous cell carcinoma (LUSC) is associated with a low survival rate. Evidence suggests that bone morphogenetic proteins (BMPs) and their receptors (BMPRs) play crucial roles in tumorigenesis and progression. However, a comprehensive analysis of their role in LUSC is lacking. Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC. METHODS: The "R/Limma" package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC, using data from TCGA, GTEx, and GEO databases. Concurrently, the "survminer" packages were employed to investigate their prognostic value and correlation with clinical features in LUSC. The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis (WGCNA). LASSO analysis was conducted to construct a prognostic risk model for LUSC. Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC. Furthermore, based on the tumor immune estimation resource database and tumor-immune system interaction database, the role of the core gene in the tumor microenvironment of LUSC was explored. RESULTS: GDF10 had a significant correlation only with the pathological T stage of LUSC, and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC. A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes (HRASLS, HIST1H2BH, FLRT3, CHEK2, and ALPL) for LUSC. GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression. CONCLUSION: GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.

Characterization of tumor evolution by functional clonality and phylogenetics in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy, and its fitness may be shaped by how its tumor cells evolve. However, ability to monitor tumor cell evolution is hampered by the presence of numerous passenger mutations that do not provide any biological consequences. Here we develop a strategy to determine the tumor clonality of three independent HCC cohorts of 524 patients with diverse etiologies and race/ethnicity by utilizing somatic mutations in cancer driver genes. We identify two main types of tumor evolution, i.e., linear, and non-linear models where non-linear type could be further divided into classes, which we call shallow branching and deep branching. We find that linear evolving HCC is less aggressive than other types. GTF2IRD2B mutations are enriched in HCC with linear evolution, while TP53 mutations are the most frequent genetic alterations in HCC with non-linear models. Furthermore, we observe significant B cell enrichment in linear trees compared to non-linear trees suggesting the need for further research to uncover potential variations in immune cell types within genomically determined phylogeny types. These results hint at the possibility that tumor cells and their microenvironment may collectively influence the tumor evolution process.

Interferon-α induces differentiation of cancer stem cells and immunosuppression in hepatocellular carcinoma by upregulating CXCL8 secretion.

Interferon-alpha (IFN-α) is widely used in the clinical treatment of patients with chronic hepatitis B and hepatocellular carcinoma (HCC). However, high levels of CXCL8 are associated with resistance to IFN-α therapy and poorer prognosis in advanced cancers. In this study, we investigated whether IFN-α could directly induce the production of CXCL8 in HCC cells and whether CXCL8 could antagonize the antitumor activity of IFN-α. We found that IFN-α not only upregulated the expression of the inducible genes CXCL9, CXCL10, CXCL11 and PD-L1, but also significantly stimulated CXCL8 secretion in HCC cells. Mechanically, IFN-α induces CXCL8 expression by activating the AKT and JNK pathways. In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic. Besides, our study reveals that the cytokine CXCL8 secreted by IFN-α-induced HCC cells inhibits T-cell function. Conversely, inhibition of CXCL8 promotes TNF-α and IFN-γ secretion by T cells. Finally, liver cancer patients who received anti-PD-1/PD-L1 immunotherapy with high CXCL8 expression had a lower immunotherapy efficacy. Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future.

Deep whole-genome analysis of 494 hepatocellular carcinomas.

Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China1-3. However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited4-8, with current analyses of HCC mainly from non-HBV-enriched populations9,10. Here we initiated the Chinese Liver Cancer Atlas (CLCA) project and performed deep whole-genome sequencing (average depth, 120×) of 494 HCC tumours. We identified 6 coding and 28 non-coding previously undescribed driver candidates. Five previously undescribed mutational signatures were found, including aristolochic-acid-associated indel and doublet base signatures, and a single-base-substitution signature that we termed SBS_H8. Pentanucleotide context analysis and experimental validation confirmed that SBS_H8 was distinct to the aristolochic-acid-associated SBS22. Notably, HBV integrations could take the form of extrachromosomal circular DNA, resulting in elevated copy numbers and gene expression. Our high-depth data also enabled us to characterize subclonal clustered alterations, including chromothripsis, chromoplexy and kataegis, suggesting that these catastrophic events could also occur in late stages of hepatocarcinogenesis. Pathway analysis of all classes of alterations further linked non-coding mutations to dysregulation of liver metabolism. Finally, we performed in vitro and in vivo assays to show that fibrinogen alpha chain (FGA), determined as both a candidate coding and non-coding driver, regulates HCC progression and metastasis. Our CLCA study depicts a detailed genomic landscape and evolutionary history of HCC in Chinese individuals, providing important clinical implications.

Single-Cell Characterization of the Tumor Ecosystem in Liver Cancer.

Tumor heterogeneity along with the complex landscape of the tumor microenvironment create critical challenges for effective liver cancer interventions. Characterizing the tumor ecosystem at the single-cell level may provide insight into the collective behaviors of tumor cells and their interplays with stromal and immune cells. Here we introduce the experimental protocol and computational methods for the single-cell study of liver cancer, which may be essential for a mechanistic understanding of the tumor ecosystem in liver cancer and further pave the way for developing novel therapeutics.

Tricuspid mechanical valve replacement for severe tricuspid stenosis in a child who underwent surgical correction of complete atrioventricular septal defect, a rare long-term complications.

BACKGROUND: Complete atrioventricular septal defect is a complicated congenital heart malformations, and surgical correction is the best treatment, the severe tricuspid stenosis is a rare long-term complication after the surgery. CASE PRESENTATION: We report a case with the complication of severe tricuspid stenosis 7 years after the surgical correction of complete atrioventricular septal defect in a child. Then the patient underwent tricuspid mechanical valve replacement, Glenn, atrial septostomy, and circumconstriction of the right pulmonary artery. CONCLUSIONS: The patient recovered successfully with good short-term.

Nanosensor detection of reactive oxygen and nitrogen species leakage in frustrated phagocytosis of nanofibres.

Exposure to widely used inert fibrous nanomaterials (for example, glass fibres or carbon nanotubes) may result in asbestos-like lung pathologies, becoming an important environmental and health concern. However, the origin of the pathogenesis of such fibres has not yet been clearly established. Here we report an electrochemical nanosensor that is used to monitor and quantitatively characterize the flux and dynamics of reactive species release during the frustrated phagocytosis of glass nanofibres by single macrophages. We show the existence of an intense prolonged release of reactive oxygen and nitrogen species by single macrophages near their phagocytic cups. This continued massive leakage of reactive oxygen and nitrogen species damages peripheral cells and eventually translates into chronic inflammation and lung injury, as seen during in vitro co-culture and in vivo experiments.