Bioinformatics-based dynamics of cuproptosis -related indicators in experimental silicosis.

Pneumoconiosis is one of the most serious occupational diseases worldwide. Silicosis due to prolonged inhalation of free silica dust during occupational activities is one of the main types. Cuproptosis is a newly discovered mode of programmed cell death characterized by the accumulation of free copper in the cell, which ultimately leads to cell death. Increased copper in the serum of silicosis patients, suggests that the development of silicosis is accompanied by changes in copper metabolism, but whether cuproptosis is involved in the progression of silicosis is actually to be determined. To test this hypothesis, we screened the genetic changes in patients with idiopathic fibrosis by bioinformatics methods and predicted and functionally annotated the cuproptosis-related genes among them. Subsequently, we established a mouse silicosis model and detected the concentration of copper ions and the activity of ceruloplasmin (CP) in serum, as well as changes of the concentration of copper and cuproptosis related genes in mouse lung tissues. We identified 9 cuproptosis-related genes among the differential genes in patients with IPF at different times and the tissue-specific expression levels of ferredoxin 1 (FDX1) and Lipoyl synthase (LIAS) proteins. Furthermore, serum CP activity and copper ion levels in silicosis mice were elevated on days 7th and 56th after silica exposure. The expression of CP in mouse lung tissue elevated at all stages after silica exposure. The mRNA level of FDX1 decreased on days 7th and 56th, and the protein level remained in accordance with the mRNA level on day 56th. LIAS and Dihydrolipoamide dehydrogenase (DLD) levels were downregulated at all times after silica exposure. In addition, Heatshockprotein70 (HSP70) expression was increased on day 56. In brief, our results demonstrate that there may be cellular cuproptosis during the development of experimental silicosis in mice and show synchronization with enhanced copper loading in mice.

Mitochondrial folate pathway regulates myofibroblast differentiation and silica-induced pulmonary fibrosis.

BACKGROUND: Silica-induced pulmonary fibrosis (silicosis) is a diffuse interstitial fibrotic disease characterized by the massive deposition of extracellular matrix in lung tissue. Fibroblast to myofibroblast differentiation is crucial for the disease progression. Inhibiting myofibroblast differentiation may be an effective way for pulmonary fibrosis treatment. METHODS: The experiments were conducted in TGF-ß treated human lung fibroblasts to induce myofibroblast differentiation in vitro and silica treated mice to induce pulmonary fibrosis in vivo. RESULTS: By quantitative mass spectrometry, we revealed that proteins involved in mitochondrial folate metabolism were specifically upregulated during myofibroblast differentiation following TGF-ß stimulation. The expression level of proteins in mitochondrial folate pathway, MTHFD2 and SLC25A32, negatively regulated myofibroblast differentiation. Moreover, plasma folate concentration was significantly reduced in patients and mice with silicosis. Folate supplementation elevated the expression of MTHFD2 and SLC25A32, alleviated oxidative stress and effectively suppressed myofibroblast differentiation and silica-induced pulmonary fibrosis in mice. CONCLUSION: Our study suggests that mitochondrial folate pathway regulates myofibroblast differentiation and could serve as a potential target for ameliorating silica-induced pulmonary fibrosis.

HMMR potential as a diagnostic and prognostic biomarker of cancer-speculation based on a pan-cancer analysis.

Background: Although the status of universal upregulation for the Hyaluronan-Mediated Motility Receptor (HMMR) in pan-cancer is still unknown, HMMR is upregulated and associated with poor prognosis for some tumors. Methods: Exploring HMMR expression in different tumor types using The Cancer Genome Atlas (TCGA) or other public databases for a pan-cancer analysis, exploring the relationship between HMMR and tumor prognosis, and exploring the role of HMMR in tumor immunity. Results: No matter the pairing or unpairing of data, HMMR expression generally increased compared to corresponding normal tissue. Based on a CCLE study, our results indicated that HMMR is widely expressed in various tumor cells. For most tumor types, high HMMR expression was associated with reduced Overall Survival (OS), Return to Functional Status (RFS), and Platinum Free Interval (PFI). ROC curves indicated that HMMR displays high prediction potential for most tumor types. In pan-cancer, HMMR is correlated with some clinical staging, immune cells, and immune checkpoints for some tumors. The GO/KEGG enrichment analysis results for proteins most closely related to HMMR indicate that the most highly enriched pathways are all related to tumor development. Conclusions: Our pan-cancer analysis of HMMR suggests that HMMR can be used as a potential diagnostic and prognostic indicator of pan-cancer and that HMMR may be involved in tumor development.

LncRNA GAS6-AS2 promotes non-small-cell lung cancer cell proliferation via regulating miR-144-3p/ MAPK6 axis.

The function of a new long non-coding RNA GAS6-AS2 in non-small cell lung cancer (NSCLC) is not fully understood. In this study, GAS6-AS2 was identified, and its roles as well as mechanisms in regulating proliferation of NSCLCs cells were investigated. qRT-PCR was used to analyze GAS6-AS2, miR-144-3p, and MAPK6 expression. Protein expression was detected by Western blotting. Cell Counting Kit-8 (CCK8) assay was used to examine the cell proliferation ability. The interaction between GAS6-AS2 and miR-144-3p was confirmed by dual-luciferase reporter assay and RNA pull down assay. A xenograft model was constructed to monitor the mice NSCLC tumor growth in vivo. GAS6-AS2 was up-regulated, while miR-144-3p was suppressed in NSCLC cells compared with normal lung cells. GAS6-AS2 suppression could inhibit the progression of NSCLC cells, and miR-144-3p could attenuate the effect. GAS6-AS2 could function as a competitive endogenous RNA (ceRNA) via direct sponging miR-144-3p-3p, which further regulating the expression of MAPK6. The knockdown of GAS6-AS2 could greatly suppress the tumor growth of NSCLC in vivo. GAS6-AS2 up-regulated MAPK6 by sponging miR-144-3p in NSCLC tissues and cells. Thus, GAS6-AS2 is an effective therapeutic target in NSCLC.

Video-assisted thoracoscopic left upper lobectomy and broncho-and-angioplasty for a giant central lung cancer complicated with intratumoral abscess: one case report.

A 70-year-old male patient with chest pain and high fever was diagnosed as lung squamous carcinoma T4N0M0 in the left upper lobe complicated with intratumoral lung abscess. With no improvement resulted from antibiotic treatment for 4 days, to control his infection and resect his large tumor, he received video-assisted thoracoscopic surgery (VATS) left upper lung lobe resection and broncho-and angioplasty. Two-port technique was employed and the utility port was 10 cm long because the tumor's diameter (max) was 12 cm. After the first step to divide the tumor from chest wall and mediastinum, the pericardium was opened and dissection was carried out in a direction from anterior to posterior meticulously. The superior pulmonary vein was divided by a stapler and then the upper bronchus cut open. Then the pulmonary artery was blocked and then its branches were cut open. At last, angioplasty and bronchoplasty was completed by sutures. Without any accidental bleeding, the whole operative time was 350 min and bleeding volume 100 mL. After the operation, fever resolved soon and pathologic stage was pT4N2M0. The patient was discharged from the hospital 20 days after the surgery. Generally, large tumor is still challenging in VATS operation and obstructive lung infection or abscess make the operation harder. However, VATS can still be applied in these patients and provide better vision and better chances for recovery without compromise of tumor principle.

Polymorphisms of the stem cell marker gene CD133 are associated the clinical outcome in a cohort of Chinese non-small cell lung cancer patients.

OBJECTIVES: To evaluate the prognostic relevance of four functional single nucleotide polymorphisms (SNPs) in CD133 (rs2240688A>C, rs10022537T>A, rs7686732C>G, and rs3130C>T) on overall survival (OS) of non-small cell lung cancer (NSCLC) patients. DESIGN: Retrospective cohort study. SETTING: Department of General Surgery, in a general hospital, Henan Province, China. PARTICIPANTS: NSCLC patients aged ≥18 years, who were not receiving preoperative neoadjuvant therapies and had a blood sample available for genotyping, were eligible for inclusion. Those participants who were pregnant or breastfeeding, had a previous history of cancer, had other primary tumours, or who had had primary tumours of the skin and nasopharynx, were excluded from the study. OUTCOME MEASURES: The primary endpoint was OS, which was calculated from the date of enrolment until the date of death or date of last follow-up. RESULTS: There was a total of 1383 participants, with a median age of 63 years; 726 (52.5%) were male. Compared with thers2240688 AA genotype, the variant AC/CC genotypes were independently associated with OS (HR 1.27, 95% CI 1.12 to 1.45 for AC genotype; HR 2.32, 95% CI 1.91 to 2.80 for CC genotype). Higher hazard ratios for associations between CD133 rs2240688 polymorphism and OS were observed in patients with adjuvant chemotherapy (HR 1.86, 95% CI 1.52 to 2.26) and radiotherapy for curative intent (HR 1.90, 95% CI 1.55 to 2.33). CONCLUSIONS: The study confirmed the significant association between the SNP rs2240688 A>C of CD133 and OS of NSCLC patients. Larger population-based studies in different ethnic groups are necessary to further validate the role and mechanisms of CD133 in NSCLC.

Polymorphisms of the Stem Cell Marker Gene CD133 and the Risk of Lung Cancer in Chinese Population.

OBJECTIVE: To explore the association of functional single-nucleotide polymorphisms (SNPs) of CD133 with the risk of lung cancer. METHODS: We conducted a hospital-based, case-control study of 1017 lung cancer patients and 1035 cancer-free controls frequency-matched by age and sex. Four functional CD133 SNPs (rs2240688 A > C, rs10022537 T > A, rs7686732 C > G, and rs3130 C > T) were selected and genotyped. Unconditional univariate and multivariate logistic regression analyses were carried out to evaluate the associations of genotypes of CD133 SNPs with lung cancer risk. RESULTS: Compared with rs2240688 AA genotype, the variant AC/CC genotypes were associated with a statistically increased risk of lung cancer under a recessive model (adjusted odds ratio 1.19; 95 % confidence interval 1.01-1.42). The risk remained in patients with other histology types, but not with adenocarcinoma and squamous cell cancers. CONCLUSIONS: These findings suggest that SNP rs2240688 A > C of CD133 may be a potential biomarker for genetic susceptibility to lung cancer, but require further research with larger populations.

Scutellaria barbata D. Don polysaccharides inhibit the growth of Calu-3 xenograft tumors via suppression of the HER2 pathway and angiogenesis.

Scutellaria barbata D. Don, a perennial herb belonging to the family Lamiaceae, is widely distributed throughout China and the Republic of Korea, and has been traditionally used in folk medicine as an antitumor and anti-inflammatory agent. Polysaccharides isolated from Scutellaria barbata D. Don (PSB), have been reported to possess antitumor effects. However, the detailed antitumor mechanisms behind the effects of PSB remain unclear. In the present study, a non-small cell lung cancer cell line harboring the HER2 gene mutation Calu-3, the Calu-3 cell line, was used to investigate the underlying mechanisms of the antitumor effects of PSB. The results revealed that PSB potently inhibited cell proliferation and human epidermal growth factor receptor (HER)2 phosphorylation in vitro, and also downregulated the expression of the downstream signaling molecules, including phosphorylated (phospho-)Akt and phospho-extracellular signal-related kinase. In vivo, PSB demonstrated efficacy at well-tolerated doses, including significant antitumor activity in a Calu-3 subcutaneous xenograft model. Immunohistochemistry (IHC) analysis revealed a PSB dose-dependent reduction of microvessel density, demonstrated by cluster of differentiation 31 staining. The present findings suggest that inhibition of tumor angiogenesis via suppression of the HER2 pathway may be one of the mechanisms by which PSB can be effective in the treatment of cancers.

[Clinical analysis of lung cancer patients younger than 30 years].

BACKGROUND AND OBJECTIVE: It is common recognized that young patients of lung cancer have poor prognosis due to relatively higher malignancy and more invasive growth. In the past most studies on young patients of lung cancer selected patients younger than 40 or 45 years old, and there were few clinical materials for younger patients under 30 years. This study retrospectively described the the disease history, stage, treatment and pathology features of lung cancer patients younger than 30 years and aimed to provide references for these patients. METHODS: Those patients younger than 30 years, once admitted in the General Hospital of the People's Liberation Army for lung cancer from 1993 to date, were sought in medical record system, and 53 patients were found in total. In this group, there were 34 non-small cell lung cancer (NSCLC) patients and 19 small cell lung cancer (SCLC) patients. The male/female ratio was 1.5:1. In the NSCLC patients, there were 27 adenocarcinomas, 6 squamous carcinomas and 1 adenosquamous carcinoma, with no large cell carcinoma involved. In these patients, 12 patients received operations while 38 patients got chemo- and/or radiotherapy and 3 quit any treatment. RESULTS: There was no death in hospital, however, in the 12 patients who got operation, only 8 patients got complete resection while 4 patients got palliative resection. CONCLUSION: Lung cancer patients younger than 30 years had a high fraction of adenocarcinoma and small cell type pathologically and most of them were in late stage when presenting with symptoms in hospital and would have a dismal prognosis. The routine health examination and early diagnosis should be emphasized to improve the prognosis of these patients.