Abstract:Serum level of miR-122 is correlated with the severity of liver injury at an early stage. miR-122 may be a potential biomarker for both the diagnosis at an early stage of CHBLF and the prognosis for recovery.
“…Circulating DNA, isolated from plasma and serum samples, is also of low quantity and quality 18 , 19 . Since in the recent past circulating mtDNA has been highlighted as a prognostic tool in cancer diagnostics 20 , 21 , our technical approach benefits from the high efficiency of whole mt-DNA sequencing (wmt-seq) on short DNA fragments. Figure 1 Scheme of primer design and the multiplex PCR-based approach to mt-genome enrichment.…”
Accurate assessment of tumour heterogeneity is an important issue that influences prognosis and therapeutic decision in molecular pathology. Due to the shortage of protective histones and a limited DNA repair capacity, the mitochondrial (mt)-genome undergoes high variability during tumour development. Therefore, screening of mt-genome represents a useful molecular tool for assessing precise cell lineages and tracking tumour history. Here, we describe a highly specific and robust multiplex PCR-based ultra-deep sequencing technology for analysis of the whole mt-genome (wmt-seq) on low quality-DNA from formalin-fixed paraffin-embedded tissues. As a proof of concept, we applied the wmt-seq technology to characterize the clonal relationship of non-small cell lung cancer (NSCLC) specimens with multiple lesions (N = 43) that show either different histological subtypes (group I) or pulmonary adenosquamous carcinoma as striking examples of a mixed-histology tumour (group II). The application of wmt-seq demonstrated that most samples bear common mt-mutations in each lesion of an individual patient, indicating a single cell progeny and clonal relationship. Hereby we show the monoclonal origin of histologically heterogeneous NSCLC and demonstrate the evolutionary relation of NSCLC cases carrying heteroplasmic mt-variants.
“…Circulating DNA, isolated from plasma and serum samples, is also of low quantity and quality 18 , 19 . Since in the recent past circulating mtDNA has been highlighted as a prognostic tool in cancer diagnostics 20 , 21 , our technical approach benefits from the high efficiency of whole mt-DNA sequencing (wmt-seq) on short DNA fragments. Figure 1 Scheme of primer design and the multiplex PCR-based approach to mt-genome enrichment.…”
Accurate assessment of tumour heterogeneity is an important issue that influences prognosis and therapeutic decision in molecular pathology. Due to the shortage of protective histones and a limited DNA repair capacity, the mitochondrial (mt)-genome undergoes high variability during tumour development. Therefore, screening of mt-genome represents a useful molecular tool for assessing precise cell lineages and tracking tumour history. Here, we describe a highly specific and robust multiplex PCR-based ultra-deep sequencing technology for analysis of the whole mt-genome (wmt-seq) on low quality-DNA from formalin-fixed paraffin-embedded tissues. As a proof of concept, we applied the wmt-seq technology to characterize the clonal relationship of non-small cell lung cancer (NSCLC) specimens with multiple lesions (N = 43) that show either different histological subtypes (group I) or pulmonary adenosquamous carcinoma as striking examples of a mixed-histology tumour (group II). The application of wmt-seq demonstrated that most samples bear common mt-mutations in each lesion of an individual patient, indicating a single cell progeny and clonal relationship. Hereby we show the monoclonal origin of histologically heterogeneous NSCLC and demonstrate the evolutionary relation of NSCLC cases carrying heteroplasmic mt-variants.
“…lncRNA, H19, which can be silenced by MeCP2, represses expression of insulin-like growth factor 1 receptor (IGF1R) and suppresses HSC proliferation [276]. Circulating cell-free miRNAs, e.g., miR-122, miR-138, miR-143, and miR-185, have been assessed as potential non-invasive biomarkers of HSC activation, liver fibrosis, and/or prognosis in patients mostly affected with HBV or HCV [277–279]. …”
Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.
“…Liver failure is a devastating disease with high morbidity and mortality. In China, the main cause of liver failure is hepatitis B virus (HBV) infection[ 2 ]. It develops rapidly and has extremely poor prognosis[ 3 ], so judging the severity and predicting the prognosis of liver failure are important.…”
BACKGROUND
Liver failure has high mortality and poor prognosis, and establishing new reliable markers for predicting its prognosis is necessary. Mucosal-associated invariant T (MAIT) cells are a novel population of innate-like lymphocytes involved in inflammatory liver disease, and their potential role in liver failure remains unclear.
AIM
To investigate alteration of circulating MAIT cells and assess its prognostic value in patients with hepatitis B virus (HBV)-related liver failure.
METHODS
We recruited 55 patients with HBV-related liver failure, 48 patients with chronic hepatitis B and 40 healthy controls (HCs) from Nantong Third People’s Hospital Affiliated to Nantong University. Peripheral blood mononuclear cells were isolated, and the percentage and number of circulating MAIT cells were detected by flow cytometry. Plasma levels of interleukin (IL)-7, IL-12p70, IL-18 and interferon-α were measured by Luminex assay.
RESULTS
Circulating MAIT cells were significantly decreased in HBV-related liver failure patients (percentage: 2.00 ± 1.22
vs
5.19 ± 1.27%,
P <
0.0001; number: 5.47 ± 4.93
vs
84.43 ± 19.59,
P <
0.0001) compared with HCs. More importantly, there was a significant reduction of MAIT cells in patients with middle/late-stage compared with early-stage liver failure. Circulating MAIT cells partially recovered after disease improvement, both in percentage (4.01 ± 1.21
vs
2.04 ± 0.95%,
P <
0.0001) and in cell count (17.24 ± 8.56
vs
7.41 ± 4.99,
P <
0.0001). The proportion (2.29 ± 1.01
vs
1.58 ± 1.38%,
P <
0.05) and number (7.30 ± 5.70
vs
2.94 ± 1.47,
P <
0.001) of circulating MAIT cells were significantly higher in the survival group than in the dead/liver transplantation group, and the Kaplan–Meier curve showed that lower expression of circulating MAIT cells (both percentage and cell count) predicted poor overall survival (
P <
0.01). Also, the levels of IL-12 (20.26 ± 5.42 pg/mL
vs
17.76 ± 2.79 pg/mL,
P =
0.01) and IL-18 (1470.05 ± 1525.38 pg/mL
vs
362.99 ± 109.64 pg/mL,
P <
0.0001) were dramatically increased in HBV-related liver failure patients compared with HCs.
CONCLUSION
Circulating MAIT cells may play an important role in the process of HBV-related liver failure and can be an important prognostic marker.
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