Kuan Yuan Chen

Escape from IFN-γ-dependent immunosurveillance in tumorigenesis

Immune interferon (IFN), also known as IFN-γ, promotes not only immunomodulation but also antimicrobial and anticancer activity. After IFN-γ binds to the complex of IFN-γ receptor (IFNGR) 1-IFNGR2 and subsequently activates its downstream signaling pathways, IFN-γ immediately causes transcriptional stimulation of a variety of genes that are principally involved in its biological activities. Regarding IFN-γ-dependent immunosurveillance, IFN-γ can directly suppress tumorigenesis and infection and/or can modulate the immunological status in both cancer cells and infected cells. Regarding the anticancer effects of IFN-γ, cancer cells develop strategies to escape from IFN-γ-dependent cancer immunosurveillance. Immune evasion, including the recruitment of immunosuppressive cells, secretion of immunosuppressive factors, and suppression of cytotoxic T lymphocyte responses, is speculated to be elicited by the oncogenic microenvironment. All of these events effectively downregulate IFN-γ-expressing cells and IFN-γ production. In addition to these extrinsic pathways, cancer cells may develop cellular tolerance that manifests as hyporesponsiveness to IFN-γ stimulation. This review discusses the potential escape mechanisms from IFN-γ-dependent immunosurveillance in tumorigenesis.

Dysfunction of methionine sulfoxide reductases to repair damaged proteins by nickel nanoparticles

BACKGROUND Protein oxidation is considered to be one of the main causes of cell death, and methionine is one of the primary targets of reactive oxygen species (ROS). However, the mechanisms by which nickel nanoparticles (NiNPs) cause oxidative damage to proteins remain unclear. OBJECTIVES The objective of this study is to investigate the effects of NiNPs on the methionine sulfoxide reductases (MSR) protein repairing system. METHODS Two physically similar nickel-based nanoparticles, NiNPs and carbon-coated NiNP (C-NiNPs; control particles), were exposed to human epithelial A549 cells. Cell viability, benzo(a)pyrene diolepoxide (BPDE) protein adducts, methionine oxidation, MSRA and B3, microtubule-associated protein 1A/1B-light chain 3 (LC3) and extracellular signal-regulated kinase (ERK) phosphorylation were investigated. RESULTS Exposure to NiNPs led to a dose-dependent reduction in cell viability and increased BPDE protein adduct production and methionine oxidation. The methionine repairing enzymatic MSRA and MSRB3 production were suppressed in response to NiNP exposure, suggesting the oxidation of methionine to MetO by NiNP was not reversed back to methionine. Additionally, LC3, an autophagy marker, was down-regulated by NiNPs. Both NiNP and C-NiNP caused ERK phosphorylation. LC3 was positively correlated with MSRA (r = 0.929, p < 0.05) and MSRB3 (r = 0.893, p < 0.05). CONCLUSIONS MSR was made aberrant by NiNP, which could lead to the dysfunction of autophagy and ERK phosphorylation. The toxicological consequences may be dependent on the chemical characteristics of the nanoparticles.

Novel biomarker analysis of pleural effusion enhances differentiation of tuberculous from malignant pleural effusion.

Lymphocytic pleurisy is commonly observed in tuberculosis and cancer. Noninvasive biomarkers are needed to distinguish tuberculous pleural effusion (TPE) from malignant pleural effusion (MPE) because current clinical diagnostic procedures are often invasive. We identified immune response biomarkers that can discriminate between TPE and MPE. Fourteen pleural effusion biomarkers were compared in 22 MPE patients and five TPE patients. Of the innate immunity biomarkers, the median levels of interleukin (IL)-1β and interferon-induced protein-10 (IP-10) were higher in TPE patients than in MPE patients (P<0.05 and P<0.01, respectively). Of the adaptive immunity biomarkers, the median levels of IL-13 and interferon-γ (IFN-γ) were higher in TPE patients than in MPE patients (P<0.05). In addition, the levels of basic fibroblast growth factor were higher in MPE patients than in TPE patients (P<0.05). Receiver operator characteristic analysis of these biomarkers was performed, resulting in the highest area under the curve (AUC) for IP-10 (AUC =0.95, 95% confidence interval, P<0.01), followed by IL-13 (AUC =0.86, 95% confidence interval, P<0.05). Our study shows that five biomarkers (IL-1β, IP-10, IFN-γ, IL-13, and basic fibroblast growth factor) have a potential diagnostic role in differentiating TPE from MPE, particularly in lung cancer-related MPE.

Pulmonary pathobiology induced by zinc oxide nanoparticles in mice: A 24-hour and 28-day follow-up study

ABSTRACT Inhaled zinc oxide nanoparticles (ZnONPs) have high deposition rates in the alveolar region of the lungs; however, the adverse health effects of ZnONPs on the respiratory system are unclear. Herein, pathobiological responses of the respiratory system of mice that received intratracheal administration of ZnONPs were investigated by a combination of molecular and imaging (SPECT and CT) approaches. Also, normal BEAS‐2B and adenocarcinoma A549 cells were used to confirm the results in mice. First, female BALB/c mice were administrated a series of doses of 20‐nm ZnONPs and were compared to the phosphate‐buffered saline control for 24‐h and 28‐day follow‐up observations. Field emission‐scanning electron microscopy and an energy‐dispersive X‐ray microanalysis were first used to characterize ZnONPs. After 24 h, instilled ZnONPs had caused significant increases in lactic dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF) and 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), caspase‐3, and the p63 tumor marker in lung tissues (p < 0.05). Airway inflammation was present in a dose‐dependent manner from the upper to the lower airway as analyzed by SPECT. After 28 days, p63 had significantly increased due to ZnONP exposure in lung tissues (p < 0.05). Pulmonary inflammatory infiltration mainly occurred in the left and right subsegments of the secondary bronchial bifurcation as observed by CT. A significant increase in p63 and decrease in TTF1 levels were observed in BEAS‐2B cells by ZnONP (p < 0.05), but not in A549 cells. Our results demonstrated that regional lung inflammation occurred with ZnONP exposure. We also showed that p63 was consistently overexpressed due to ZnONP exposure in vivo and in vitro. This work provides unique findings on the p63 response and the pathobiology in response to ZnONPs, which could be important to the study of pulmonary toxicity and repair. HighlightsPulmonary effects caused by ZnONPs are determined in mice.Acute lung injury, lower airway inflammation, and p63 expression are observed.Pulmonary infiltration occurred by ZnONP at the secondary bronchial bifurcation.p63 was consistently over‐expressed at 24 h and 28 days after ZnONP exposure.

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB

Background Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient’s MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. Conclusions In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway. Methods Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

Trace Elements in Pleural Effusion Correlates with Smokers with Lung Cancer

Smoking leads to the presence of various elements, including toxic metals and metalloids, in tissues and fluids, thus contributing to cancer risk. This study assessed the concentrations of 14 elements (Ag, Al, As, Co, Cr, Cu, Fe, Ni, Mn, Mo, Pb, Sn, V, and Zn) and biochemical parameters (glucose, lactate dehydrogenase, and total protein) in the pleural effusion (PE) of patients with lung cancer. The potential association of these parameters with smoking was assessed. Total of 48 patients with lung cancer (26 non-smokers and 22 smokers) received thoracocentesis for PE removal. Analysis results revealed that among the biochemical parameters, only the glucose concentration was significantly higher in current smokers than in non-smokers; the other parameters showed no significant difference. The concentration of Zn in the PE was significantly lower in all smokers (10 former and 12 current smokers) than in non-smokers, but the other elements did not differ significantly between the two groups and smoker subgroups. Simultaneously, Zn correlated negatively with glucose concentrations in all smokers, positively with lactate dehydrogenase (LDH) concentration in current smoker, and positively with total protein (TP) concentrations in non-smokers. This is for the first time the relation between Zn and certain biochemical parameters in PE was found, the observation requiring further studies to explain the potential interactions between this element and glucose, LDH, and TP concentrations.

Investigation into the pulmonary inflammopathology of exposure to nickel oxide nanoparticles in mice

We investigated the effects of nickel oxide nanoparticles (NiONPs) on the pulmonary inflammopathology. NiONPs were intratracheally installed into mice, and lung injury and inflammation were evaluated between 1 and 28 days. NiONPs caused significant increases in LDH, total protein, and IL-6 and a decrease in IL-10 in the BALF and increases in 8-OHdG and caspase-3 in lung tissues at 24 h. Airway inflammation was present in a dose-dependent manner from the upper to lower airways at 24 h of exposure as analyzed by SPECT. Lung parenchyma inflammation and small airway inflammation were observed by CT after NiONP exposure. 8-OHdG in lung tissues had increased with formation of fibrosis at 28 days. Focal adhesion was the most important pathways identified at 24 h as determined by protemics, whereas glutathione metabolism was the most important identified at 28 days. Our results demonstrated the pulmonary inflammopathology caused by NiONPs based on image-to-biochemical approaches.

Proteasome activity related with the daily physical activity of COPD patients

Background COPD is a debilitating disease that affects patients’ daily lives. One’s daily physical activity (DPA) decreases due to multifactorial causes, and this decrease is correlated with a poor prognosis in COPD patients. Muscle wasting may at least be partly due to increased activity of the ubiquitin proteasome pathway and apoptosis. Methods This study investigated the relationships among DPA, circulating proteasome activity, and protein carbonyl in COPD patients and healthy subjects (HSs). This study included 57 participants (42 patients and 15 healthy subjects). Ambulatory DPA was measured using actigraphy, and oxygen saturation was measured with a pulse oximeter. Results COPD patients had lower DPA, lower 6 min walking distance (6MWD), lower delta saturation pulse oxygenation (SpO2) during the 6MWT, and lower delta SpO2 during DPA than HSs. COPD patients had higher proteasome activity and protein carbonyl than HSs. Circulating proteasome activity was significantly negatively correlated with DPA (r=−0.568, P<0.05) in COPD patients, whereas delta SpO2 during the 6MWT was significantly positively correlated with proteasome activity (r=0.685, P<0.05) in HSs. Protein carbonyl was significantly negatively correlated with the body mass index (r=−0.318, P<0.05), mid-arm circumference (r=0.350, P<0.05), calf circumference (r=0.322, P<0.05), forced expiratory volume in the first second (r=-0.441, P<0.01), and 6MWD (r=−0.313, P<0.05) in COPD patients. Our results showed no significant difference in inflammatory markers (interleukin-6 and tumor necrosis factor-α) or ubiquitin between the two groups. Conclusion COPD patients had lower DPA levels and higher circulating proteasome activity than HSs, and a negative correlation of DPA with circulating proteasome activity.

Particulate matter is associated with sputum culture conversion in patients with culture-positive tuberculosis

Emerging risk factors for tuberculosis (TB) infection, such as air pollution, play a significant role at both the individual and population levels. However, the association between air pollution and TB remains unclear. The objective of this study was to examine the association between outdoor air pollution and sputum culture conversion in TB patients. In the present study, 389 subjects were recruited from a hospital in Taiwan from 2010 to 2012: 144 controls with non-TB-related pulmonary diseases with negative sputum cultures and 245 culture-positive TB subjects. We observed that a 1 μg/m3 increase in particulate matter of ≤10 μm in aerodynamic diameter (PM10) resulted in 4% higher odds of TB (odds ratio =1.04, 95% confidence interval =1.01–1.08, P<0.05). The chest X-ray grading of TB subjects was correlated to 1 year levels of PM10 (R2=0.94, P<0.05). However, there were no associations of pulmonary cavitation or treatment success rate with PM10. In subjects with TB-positive cultures, annual exposure to ≥50 μg/m3 PM10 was associated with an increase in the time required for sputum culture conversion (hazard ratio =1.28, 95% confidence interval: 1.07–1.84, P<0.05). In conclusion, chronic exposure to ≥50 μg/m3 PM10 may prolong the sputum culture conversion of TB patients with sputum-positive cultures.

Correction: S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: The role of RELB [Oncotarget., 9, (2018), (7631-7643)] DOI: 10.18632/oncotarget.24146

[This corrects the article DOI: 10.18632/oncotarget.24146.].