Neutralization of interleukin-11 attenuates silica particles-induced pulmonary inflammation and fibrosis in vivo.

Environmental exposure to crystalline silica particles can lead to silicosis, which is one of the most serious pulmonary interstitial fibrosis around the world. Unfortunately, the exact mechanism on silicosis is unclear, and the effective treatments are lacking to date. In this study, we aim to explore the molecular mechanism by which interleukin-11 (IL-11) affects silica particles-induced lung inflammation and fibrosis. We observed that IL-11 expressions in mouse lungs were significantly increased after silica exposure, and maintained at high levels across both inflammation and fibrosis phase. Immunofluorescent dual staining further revealed that the overexpression of IL-11 mainly located in mouse lung epithelial cells and fibroblasts. Using neutralizing anti-IL-11 antibody could effectively alleviate the overexpression of pro-inflammatory cytokines (i.e., interleukin-6 and tumor necrosis factor-α) and fibrotic proteins (i.e., collagen type I and matrix metalloproteinase-2) induced by silica particles. Most importantly, the expressions of IL-11 receptor subunit α (IL-11Rα), Glycoprotein 130 (GP130), and phosphorylated extracellular signal-regulated kinase (p-ERK) were significantly increased in response to silica, whereas blocking of IL-11 markedly reduced their levels. All findings suggested that the overexpression of IL-11 was involved in the pathological of silicosis, while neutralizing IL-11 antibody could effectively alleviate the silica-induced lung inflammation and fibrosis by inhibiting the IL-11Rα/GP130/ERK signaling pathway. IL-11 might be a promising therapeutic target for lung inflammation and fibrosis caused by silica particles exposure.

Underlying mechanisms of phosphodiesterase 10A and glutamate-ammonia ligase genes that regulate inosine monophosphate deposition and thereby affect muscle tenderness in Jingyuan chickens.

OBJECTIVE: Inosine monophosphate (IMP) is a key factor that imparts of meat flavor. Differences in the IMP content in the muscles were evaluated to improve chicken meat quality. METHODS: For this study, the IMP content was detected by high performance liquid chromatography. The gene expression profiles of Jingyuan chickens with different feeding patterns and different sexes were analyzed by RNA-sequencing (RNA-seq). RESULTS: Breast muscle IMP content in free-range chickens was extremely significantly higher than that of caged chickens (p<0.01). Breast muscle IMP content in hens was also higher than that of cocks, but the difference was not significant. Correlation analysis showed that the breast muscle IMP content in caged hens and cocks was negatively correlated with the shear force, and the breast muscle IMP content in free-range hens was significantly negatively correlated with the shear force (p<0.05). The two key genes associated with IMP synthesis in chickens with different feeding patterns were glutamate-ammonia ligase (GLUL) and phosphodiesterase 10A (PDE10A). Bioinformatics analysis revealed that the GLUL and PDE10A genes are involved in glutamine biosynthesis and purine salvage pathways respectively. In addition, GLUL expression was positively correlated with the IMP content in caged and free-range chickens, and PDE10A expression was significantly positively correlated with the IMP content in caged and free-range chickens (p<0.05). CONCLUSION: These findings will facilitate the comprehension of the deposition of IMP in the muscles and thereby aid the process of selection and breeding of good quality local chickens.

Surgical Resection of Pancreatic Hepatoid Carcinoma Followed by Combined Transarterial Chemoembolization and Immunotherapy: A Case Report.

Pancreatic hepatoid carcinoma (HC) is a heterogeneous tumor with high degree of malignancy and poor prognosis, which display cytological and/or structural features of focal hepatocellular carcinoma (HCC). For the low incidence and atypical clinical symptoms, it is possible to be diagnosed as pancreatic cancer before operation, and mainly depending on the pathological examination. To the best of our knowledge, surgery combined with radiotherapy and chemotherapy is the common treatment of pancreatic HC. However, the curative effect and prognosis is poor. We report a case of 44-year-old woman with pancreatic HC treated with PD-1 receptor inhibitor and transarterial chemoembolization, whose clinical symptoms and laboratory indexes are significantly improved after treatment.

Anticancer Effect of Biodegradable Magnesium on Hepatobiliary Carcinoma: An In Vitro and In Vivo Study.

Biliary-stent implantation has become an effective treatment for patients with malignant obstructive jaundice caused by hepatobiliary carcinoma. Stent restenosis due to tumor ingrowth is a common problem. In this study, we assessed a biodegradable form of magnesium (Mg) for its anticancer effect on hepatobiliary carcinoma, compared to the conventional stent material of titanium (Ti). The results showed that a Mg extract inhibited proliferation and induced apoptosis in human cholangiocarcinoma cells, while a Mg plate inhibited cell adhesion and destroyed the cytoskeleton in the process of biodegradation. In animal experiments with H22 tumor-bearing mice, Mg wires implanted in tumors exhibited an inhibitory effect on their growth compared with Ti wires. Fifteen days after implantation of metal wires, the mean tumor volume and weight in the Mg group were significantly smaller than in the Ti group. We observed the dynamic-degradation process of Mg wires in tumors and generation of H2 gas via soft X-ray photography and scanning electron microscopy. Histopathological analyses showed that apoptosis of tumor cells around Mg wires significantly increased, expression of carbonic anhydrase 9 significantly decreased, and the upstream protein hypoxia-inducible factor 1-alpha also decreased to some extent. Taken together, these results indicated that biodegradable Mg had antitumor properties both in vitro and in vivo, suggesting its potential application as a novel material for biodegradable biliary stents.

Enhanced Photothermal-Photodynamic Therapy by Indocyanine Green and Curcumin-Loaded Layered MoS2 Hollow Spheres via Inhibition of P-Glycoprotein.

PURPOSE: P-glycoprotein (P-gp), which is highly expressed in liver cancer cells, is one of the obstacles for the treatment of cancer. In this study, we have prepared and characterized a kind of novel ICG&Cur@MoS2 (ICG and Cur represent indocyanine green and curcumin, respectively) nanoplatform, which can achieve photothermal-photodynamic therapy and inhibit the P-gp effectively and safely. METHODS: In this work, plenty of studies including drug release, acute toxicity, Western blot, real-time PCR, cell viability, therapeutic experiment in vivo, immunofluorescence and so on were conducted to test the antitumor potential of ICG&Cur@MoS2 and the inhibitory effect of curcumin on P-gp. RESULTS: The ICG&Cur@MoS2 NPs exhibit an excellent photothermal effect and relatively low toxicity. Cell viability in the ICG&Cur@MoS2 + NIR group was significantly lower than that in ICG@MoS2 + NIR group (75.3% vs 81.2%, 59.0% vs 64.4%, 20.3% vs 27.5%, and 15.4% vs 22.3%) at the concentration of ICG at 0.5, 5, 25, 50 µg/mL (P<0.05 at each concentration). Western blot, Q-PCR, and immunofluorescence assay indicate ICG&Cur@MoS2 NPs can inhibit the P-gp effectively and safely. In vivo, the tumors in the ICG@MoS2 + NIR group are significantly smaller than those in the MoS2 + NIR group (95.0 vs 420.9 mm3, p<0.05). CONCLUSION: In conclusion, we have successfully synthesized ICG&Cur@MoS2 nanoparticles which can not only achieve PTT-PDT but also inhibit P-gp effectively. Our findings indicate that the PTT-PDT exhibits great potential in the treatment of hepatocellular carcinoma. Meanwhile, ICG&Cur@MoS2 can effectively inhibit the expression of P-gp, which will enhance the PDT effect.

Evaluation of the efficacy and postoperative outcomes of hydrodissection-assisted microwave ablation for subcapsular hepatocellular carcinoma and colorectal liver metastases.

PURPOSE: To explore the effect of hydrodissection assisted percutaneous microwave ablation (MWA) on the primary technique efficacy (PTE) and local tumor progression (LTP) of subcapsular hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM). METHODS: A retrospective review of 135 patients with 181 hepatic subcapsular HCC and CRLM that underwent MWA with (hydrodissection group) and without the use of hydrodissection (control group). The PTE, cumulative LTP rate, and postoperative complications were compared between the two groups. RESULTS: Amongst the 135 patients with 181 tumors, 60 patients with 72 tumors were in the hydrodissection group and 75 patients with 109 tumors were in the control group. The PTEs were 97.2% and 85.3% in hydrodissection and control groups, respectively (P = 0.019). Multivariate analysis showed that hydrodissection significantly improved the PTE of MWA [odds ratio (OR) 0.147; 95% confidence interval (CI) 0.031-0.703; P = 0.016). Among the tumors which achieved complete response at the first (1 month) follow-up, the overall LTP rates were 8.6% (6/70) and 11.8% (11/93) in the hydrodissection and control groups, respectively. The 1- and 2-year cumulative LTP rates were 3.0% and 5.0% for the hydrodissection group and 6.8% and 13.5% in the control group, respectively (P = 0.391). No significant differences were observed in major postoperative complications between the two groups. CONCLUSION: Hydrodissection-assisted MWA had a significantly higher PTE than MWA alone in hepatic subcapsular HCC and CRLM. Hydrodissection did not significantly impact the cumulative LTP rate or the incidence of postoperative complications.

Pictorial Imaging-Histopathology Correlation in a Rabbit with Hepatic VX2 Tumor Treated by Transarterial Vascular Disrupting Agent Administration.

Cancer vasculature is immature, disorganized and hyperpermeable and can serve as a target for anti-cancer therapies. Vascular disrupting agents (VDAs) are tubulin protein binding and depolymerizing agents that induce rapid tumoral vascular shutdown and subsequent cancer necrosis. However, two clinical problems exist with all VDAs, i.e. 1) incomplete anticancer effect and 2) dose-dependent toxicity. To tackle these problems, in our ongoing research, a novel VDA C118P is applied by transarterial administration of half the intravenous dose in rabbits with implanted VX2 liver tumor to assess its therapeutic efficacy. Nearly complete tumor necrosis was achieved by only a single arterial dose of C118P at 5 mg/kg, which was documented in a representative case by in vivo digital subtraction arteriogram (DSA) and magnetic resonance imaging (MRI), and further confirmed by ex vivo microangiogram and histopathology. This convincing and promising preliminary outcome would warrant further comprehensive studies to explore the potentials of VDAs by transarterial administration either in mono-drug or in combination for management of solid cancers.

TACE combined with microwave ablation therapy vs. TACE alone for treatment of early- and intermediate-stage hepatocellular carcinomas larger than 5 cm: a meta-analysis.

There are many therapeutic options for primary hepatocellular carcinoma (HCC), but very limited options for unresectable HCC with a single lesion larger than 5 cm (Barcelona Clinic Liver Cancer [BCLC] stage A) or with 2-3 nodules beyond 5 cm (BCLC stage B). Transcatheter arterial chemoembolization (TACE) is considered the first-line treatment for these patients, and combination therapy has also been tried. However, the effectiveness of microwave ablation (MWA) combined with TACE in the treatment of the above tumors remains to be further confirmed. Therefore, this meta-analysis aimed to compare the effectiveness of combination therapy and TACE monotherapy on these patients. PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure, and the Wan Fang electronic databases were retrieved to search for studies comparing combination therapy and TACE monotherapy, published between the earliest available date and August 20, 2019. A total of 20 articles (reporting 1736 patients) were included. Meta-analysis showed that, compared to TACE alone, TACE + MWA resulted in significantly higher 1-, 2-, and 3-year overall survival (OS) (1-year OS rate: RR = 1.36, 95% CI 1.28-1.44, P < 0.001; 2-year OS rate: RR = 1.56, 95% CI 1.40-1.74, P < 0.001 and 3-year OS rate: RR = 2.07, 95% CI: 1.67-2.57, P < 0.001). Complete response, partial response, and objective response rates were significantly higher in TACE + MWA than those in TACE alone (P < 0.001). Meanwhile, publication bias and sensitivity analysis were performed and did not show statistical significance.

Polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans exposure and altered lung function: The mediating role of oxidative stress.

The lung has been reported to be one of the target organs of polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans (PCDD/Fs) in many toxicological studies. While the associations between PCDD/Fs exposure and lung function levels have not been investigated thoroughly. This study aimed to explore these associations and the potential mediating role of oxidative stress. In this study, 201 foundry workers and 222 non-exposed general residents were recruited from central China, and their lung function parameters were measured. Air and food samples were collected to determine the PCDD/Fs levels for individual PCDD/Fs exposure estimation. Serum PCDD/Fs levels were determined in a subgroup of individuals randomly selected from the study population to reflect the body burden. It was found that each 1-unit increase in ln-transformed concentration of PCDD/Fs exposure (fg TEQ/bw/day) was associated with a 0.47 L decrease in FVC and a 0.25 L decrease in FEV1. Each 1-unit increase in ln-transformed concentration of serum PCDD/Fs (fg TEQ/g lipid) was associated with a 0.36 L decrease in FVC and a 0.24 L decrease in FEV1. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was not only positively related to PCDD/Fs exposure, but also inversely associated with FVC and FEV1 are FVC (ß = -0.15, 95% CI: -0.22 to -0.08) and FEV1 (ß = -0.07, 95% CI: -0.13 to -0.02). Mediation analysis revealed that urinary 8-OHdG mediated 12.22% of the associations of external PCDD/Fs exposure with FVC levels, 28.61% and 27.87% of the associations of serum PCDD/Fs with FVC and FEV1 levels respectively. Our findings suggested that PCDD/Fs exposure was associated with decreased lung function levels by a mechanism partly involving oxidatively generated damage to DNA.

Associations between polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans exposure and oxidatively generated damage to DNA and lipid.

Polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans (PCDD/Fs) have been reported to induce reactive oxygen species and oxidative stress, but the dose-response relationships have not been explored in molecular epidemiological studies. In this study, a total of 602 participants were recruited, comprising of 215 foundry workers, 171 incineration workers and 216 residents living more than 5 km away from the plants as the reference group. Individual PCDD/Fs exposures were estimated according to PCDD/Fs levels of working and living ambient air and daily foods. Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-iso-prostaglandin-F2α (8-isoPGF2α) were determined to reflect oxidatively generated damage to DNA and lipid. Generalized linear models were used to access the associations between PCDD/Fs exposure and oxidative stress biomarkers. We found that PCDD/Fs exposure and urinary oxidative stress biomarkers of workers were all higher than those of the reference group. Significantly positive exposure-response relationships between individual PCDD/Fs exposures and urinary 8-oxodG and 8-iso-PGF2α were found. Each 1-unit increase in ln-transformed levels of PCDD/Fs exposure generated a 0.78 nmol/mmol creatinine increase in ln-transformed 8-oxodG and a 0.50 ng/mmol creatinine increase in ln-transformed 8-isoPGF2α in foundry workers, a 0.49 nmol/mmol creatinine increase in ln-transformed 8-oxodG and a 0.26 ng/mmol creatinine increase in ln-transformed 8-isoPGF2α in incineration workers, compared with the reference group. And such associations were not modified by tobacco use. Our findings could help to understand the dose-response relationships between PCDD/Fs and oxidatively generated damage to DNA and lipid, and provide an epidemiologic basis for conducting research on the carcinogenesis and other toxicity mechanisms of PCDD/Fs.

Associations of Exhaled Carbon Monoxide and Fractional Exhaled Nitric Oxide with Metabolic Syndrome: A Cohort Study.

Exhaled carbon monoxide (eCO) and fractional exhaled nitric oxide (FeNO) could reflect underlying inflammatory and oxidative stresses, which play important roles in pathogenetic pathways of metabolic syndrome (MetS). However, epidemiologic evidence was limited. We conducted a study in Wuhan-Zhuhai (WHZH) cohort of 3649 community participants to investigate the association between eCO, FeNO and MetS in both cross-sectional and prospective ways. The results showed that higher eCO and FeNO were associated cross-sectionally with a higher prevalence of MetS. The multivariable-adjusted odds ratios for MetS at baseline were 1.22 (95% confidence interval [CI]: 1.11 to 1.35) associated with per log eCO and 1.14 (95% CI: 1.00 to 1.30) associated with per log FeNO. During a follow-up of 3 years, 358/2181 new developed MetS cases were identified. Compared with lowest quartile of eCO and FeNO, the multivariable-adjusted risk ratios (95% CI) for MetS were 1.48 (1.06 to 2.06) related to the highest quartile of eCO. These findings remained consistent across sex but not smoking status, eCO was only associated with MetS in non-smokers when stratified by smoking status. In conclusion, our study demonstrated that eCO and FeNO were independently and positively associated with the prevalence of MetS cross-sectionally, while only eCO was positively related with the incidence of MetS prospectively.

[Comparison of two methods for fiber count concentration determination].

OBJECTIVE: To compare the determination methods of fiber number concentration between China and WHO. METHODS: Individual fiber samplings were conducted at a RCF manufacturing enterprise for 40 types of work. Flow rate was set as 2 L/min and lasted 2 to 4 hours. We used acetone-triacetin to prepare samples. The rules of two methods were used to count fibers for each sample respectively. The differences between the results of two methods were compared using the sign-rank test, and the correlation between the two methods' counting results were evaluated by the Spearsman rank correlation analysis. RESULTS: The results of WHO counting rule were higher than those of Chinese counting rule for the same sample. The ratios of WHO method to Chinese method ranged from 1.88 to 3.70. Paired sign-rank test found the statistically significant differences of the results between the two methods (P<0.01). The rank correlation coefficient of the results by two rules counting ranged between 0.621 to 0.975, suggested positive correlation (P<0.01). The possible reasons of the difference between the two methods included the difference between the shapes of asbestos fiber and man-made mineral fiber, and counting rules of two methods. CONCLUSION: The results of WHO counting method is higher than those of Chinese counting method. High correlations between the results of the two methods were observed.