Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the SERPINA1 gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function.
MicroRNAs (miRNAs), key regulators of gene expression at the post-transcriptional level, are grossly misregulated in some human cancers, including non-small-cell lung carcinoma (NSCLC). The aberrant expression of specific miRNAs results in the abnormal regulation of key components of signalling pathways in tumour cells. MiRNA levels and the activity of the gene targets, including oncogenes and tumour suppressors, produce feedback that changes miRNA expression levels and indicates the cell’s genetic activity. In this study, we measured the expression of five circulating miRNAs (miR-195, miR-504, miR-122, miR-10b and miR-21) and evaluated their association with
EPIDERMAL GROWTH FACTOR RECEPTOR
(
EGFR
) mutation status in 66 NSCLC patients. Moreover, we examined the discriminative power of circulating miRNAs for
EGFR
mutant‐positive and -negative NSCLC patients using two different data normalisation approaches. We extracted total RNA from the plasma of 66 non-squamous NSCLC patients (31 of whom had tumours with
EGFR
mutations) and measured circulating miRNA levels using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The miRNA expression levels were normalised using two endogenous controls: miR-191 and miR-16. We found significant associations between the expression of circulating miR-504 and
EGFR
-activating mutations in NSCLC patients regardless of the normalisation approach used (
p
= 0.0072 and 0.0236 for miR-16 and miR-191 normalisation, respectively). The greatest discriminative power of circulating miR-504 was observed in patients with
EGFR
exon 19 deletions versus wild-type
EGFR
normalised to miR-191 (area under the curve (AUC) = 0.81,
p
< 0.0001). Interestingly, circulating miR-504 levels were significantly reduced in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (
KRAS
)-mutated subgroup compared to
EGFR
-mutated patients (
p
< 0.0030) and those with
EGFR/KRAS
wild-type tumours (
p
< 0.0359). Our study demonstrated the feasibility and potential diagnostic value of plasma miR-504 expression analysis to distinguish between
EGFR
-mutated and wild-type NSCLC patients. However, quality control and normalisation strategies are very important and have a major impact on the outcomes of circulating miRNA analyses.
while patients with lung metastasis showed longer OS than those without lung metastasis (36.0 months vs. 28.6 months, p¼0.038). Multivariable Cox regression analysis showed presence of liver metastasis (HR[hazard ratio]: 2.265, 95% CI [confidence interval]: 1.239-4.139, p¼0.008) and brain metastasis (HR: 1.496, 95% CI: 0.963-2.080, p¼0.043) were independent risk factors for OS, and presence of lung metastasis (HR: 0.669, 95% CI: 0.460-0.971, p¼0.034) was an independent protective factor for OS. Among patients with liver, brain or lung metastasis, patients with liver metastasis had the worst OS followed by patients with brain metastasis, while patients with lung metastasis had the best OS. Conclusion: The presence of liver and brain metastasis predicts unfavorable OS, and lung metastasis predicts favorable OS in EGFR-mutated stage IV NSCLC patients receiving icotinib as first-line setting. Our work provides insight into the prognostic value of presence of metastasis to different organs at diagnosis in EGFR-mutated stage IV NSCLC patients receiving icotinib as first-line setting, which might be helpful for disease management in stratifying patients prior to first-line icotinib treatment.
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