Video dataset containing video quality assessment scores obtained from standardized objective and subjective testing.

This paper presents a dataset comprising 700 video sequences encoded in the two most popular video formats (codecs) of today, H.264 and H.265 (HEVC). Six reference sequences were encoded under different quality profiles, including several bitrates and resolutions, and were affected by various packet loss rates. Subsequently, the image quality of encoded video sequences was assessed by subjective, as well as objective, evaluation. Therefore, the enclosed spreadsheet contains results of both assessment approaches in a form of MOS (Mean Opinion Score) delivered by the absolute category ranking (ACR) procedure, SSIM (Structural Similarity Index Measure) and VMAF (Video Multimethod Assessment Fusion). All assessments are available for each test sequence. This allows a comprehensive evaluation of coding efficiency under different test scenarios without the necessity of real observers or a secure laboratory environment, as recommended by the ITU (International Telecommunication Union). As there is currently no standardized mapping function between the results of subjective and objective methods, this dataset can also be used to design and verify experimental machine learning algorithms that contribute to solving the relevant research issues.

Downregulation of Glis3 in INS1 cells exposed to chronically elevated glucose contributes to glucotoxicity-associated ß cell dysfunction.

Chronically elevated levels of glucose are deleterious to pancreatic ß cells and contribute to ß cell dysfunction, which is characterized by decreased insulin production and a loss of ß cell identity. The Krüppel-like transcription factor, Glis3 has previously been shown to positively regulate insulin transcription and mutations within the Glis3 locus have been associated with the development of several pathologies including type 2 diabetes mellitus. In this report, we show that Glis3 is significantly downregulated at the transcriptional level in INS1 832/13 cells within hours of being subjected to high glucose concentrations and that diminished expression of Glis3 is at least partly attributable to increased oxidative stress. CRISPR/Cas9-mediated knockdown of Glis3 indicated that the transcription factor was required to maintain normal levels of both insulin and MafA expression and reduced Glis3 expression was concomitant with an upregulation of ß cell disallowed genes. We provide evidence that Glis3 acts similarly to a pioneer factor at the insulin promoter where it permissively remodels the chromatin to allow access to a transcriptional regulatory complex including Pdx1 and MafA. Finally, evidence is presented that Glis3 can positively regulate MafA transcription through its pancreas-specific promoter and that MafA reciprocally regulates Glis3 expression. Collectively, these results suggest that decreased Glis3 expression in ß cells exposed to chronic hyperglycemia may contribute significantly to reduced insulin transcription and a loss of ß cell identity.

Specific reprogramming of alpha cells to insulin-producing cells by short glucagon promoter-driven Pdx1 and MafA.

Endogenous reprogramming of pancreas-derived non-beta cells into insulin-producing cells is a promising approach to treat type 1 diabetes (T1D). One strategy that has yet to be explored is the specific delivery of insulin-producing essential genes, Pdx1 and MafA, to pancreatic alpha cells to reprogram the cells into insulin-producing cells in an adult pancreas. In this study, we used an alpha cell-specific glucagon (GCG) promoter to drive Pdx1 and MafA transcription factors to reprogram alpha cells to insulin-producing cells in chemically induced and autoimmune diabetic mice. Our results showed that a combination of a short glucagon-specific promoter with AAV serotype 8 (AAV8) can be used to successfully deliver Pdx1 and MafA to pancreatic alpha cells in the mouse pancreas. Pdx1 and MafA expression specifically in alpha cells were also able to correct hyperglycemia in both induced and autoimmune diabetic mice. With this technology, targeted gene specificity and reprogramming were accomplished with an alpha-specific promotor combined with an AAV-specific serotype and provide an initial basis to develop a novel therapy for the treatment of T1D.

A family with partially penetrant multicentric carpotarsal osteolysis due to gonadal mosaicism: First reported case.

Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant condition characterized by carpal-tarsal abnormalities; over half of affected individuals also develop renal disease. MCTO is caused by mutations of MAFB; however, there is no clear phenotype-genotype correlation. We describe the first reported family of variable MCTO phenotype due to mosaicism: the proband had classical skeletal features and renal involvement due to focal segmental glomerulosclerosis (FSGS), and the father had profound renal impairment due to FSGS, necessitating kidney transplantation. Mosaicism was first suspected in this family due to unequal allele ratios in the sequencing chromatograph of the initial blood sample of proband's father and confirmed by sequencing DNA extracted from the father's hair, collected from different bodily parts. This case highlights the need for a high index of clinical suspicion to detect low-level parental mosaicism, as well as a potential role for MAFB mutation screening in individuals with isolated FSGS.

Multicentric carpotarsal osteolysis syndrome (MCTO) with generalized high bone turnover and high serum RANKL: Response to denosumab.

MCTO is a rare disorder, caused by mutations in the MafB gene, a negative regulator of receptor activator of nuclear factor-кB ligand (RANKL). Manifestations include carpal and tarsal osteolysis and renal failure. Pathophysiology is poorly understood, and no effective treatment is available. In this case report we describe a patient with MCTO (MafB, mutation c.206C>T, p.Ser69Leu), diagnosed at the age of 5 years. At 7 years, skeletal survey showed diffuse osteopenia. BMD was mildly reduced, and bone turnover markers increased. He was treated with denosumab, a human monoclonal RANKL inhibitor for two years. Each injection was followed by a marked reduction in C-telopeptide (CTX). Following denosumab his BMD and bone symptoms improved and the osteolysis stabilized. At the age of 13 years, osteoporosis was diagnosed using high resolution peripheral quantitative computed tomography (HRpQCT) and serum RANKL was found to be markedly increased. This initial experience suggests that the associated osteoporosis may be ameliorated by denosumab, although further study will be needed to understand the appropriate dose, frequency, and the extent of efficacy. Monitoring of CTX and bone specific alkaline phosphatase will be especially useful in this regard. Further study in other MCTO patients is also needed to determine whether high bone turnover is specific to this mutation or more common than previously appreciated. We propose a model in which osteolysis in this condition is strongly associated with the systemic osteoporosis.

Application of "omics" sciences to the prediction of bone metastases from breast cancer: State of the art.

Breast cancer (BC) is the most frequent malignancy and the first cause of cancer-related death in women. The majority of patients with advanced BC develop skeletal metastases which may ultimately lead to serious complications, termed skeletal-related events, that often dramatically impact on quality of life and survival. Therefore, the identification of biomarkers able to stratify BC patient risk to develop bone metastases (BM) is fundamental to define personalized diagnostic and therapeutic strategies, possibly at the earliest stages of the disease. In this regard, the advent of "omics" sciences boosted the investigation of several putative biomarkers of BC osteotropism, including deregulated genes, proteins and microRNAs. The present review revisits the current knowledge on BM development in BC and the most recent studies exploring potential BM-predicting biomarkers, based on the application of omics sciences to the study of primary breast malignancies.

LncRNA TUG1 positively regulates osteoclast differentiation by targeting v-maf musculoaponeurotic fibrosarcoma oncogene homolog B.

Osteoclast differentiation-mediates bone resorption is the key biological basis of orthodontic treatment while the specific mechanism of osteoclastogenesis remains unclear. This study aims to explore the underlying mechanism of the osteoclast differentiation from the perspective of long non-coding RNA (LncRNA). In the present study, the osteoclast differentiation of CD14+ peripheral blood mononuclear cells (PBMCs) was induced by recombinant human macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL), and LncRNA TUG1 expression was dramatically elevated during this process. Functionally, the silence of TUG1 in CD14+ PBMCs decreased tartrate-resistant acid phosphatase (TRAP)-positive cell numbers and the protein levels of TRAP, nuclear factor of activated T cell c1 (NFATc1), and osteoclast-associated receptor (OSCAR), whereas increased V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MafB) protein level. The subsequent experiments confirmed that TUG1 lessened the MafB protein level via accelerating its degradation. Then, the interference of MafB reversed the inhibitory effect of si-TUG1 on osteoclastogenesis, including increased the TRAP-positive cell numbers and up-regulated the protein levels of osteoclast markers. Finally, the in vivo experiments displayed that the increased TUG1 levels could promote tooth movement and bone resorption via facilitating osteoclast differentiation in the rat model of orthodontic tooth movement. In summary, TUG1 overexpressed during the process of osteoclast differentiation and positively regulated osteoclast differentiation by targeting MafB.

Reprogramming of CaCo2 colorectal cancer cells after using the complex of poly-(N-vinylpyrrolidone) with small non-coding RNAs.

Small non-coding RNAs control normal development and differentiation in the embryo. These regulatory molecules play a key role in the development of human diseases and are used often today for researching new treatments for different pathologies. In this study, CaCo2 colorectal adenocarcinoma cells were initially epigenetically reprogrammed and transformed into CD4+ cells with nano-sized complexes of amphiphilic poly-(N-vinylpyrrolidone) (PVP) with miRNA-152 and piRNA-30074. The transformation of cells was confirmed by morphological and genetic changes in the dynamic of reprogramming. CD4+ lymphocytes marker was detected using immunofluorescence. Amphiphilic poly-(N-vinylpyrrolidone)/small non-coding RNAs complexes were investigated for transfection efficiency and duration of transfection of CaCo2 colorectal adenocarcinoma cells using fluorescence.

The role of biomarkers in the management of bone-homing malignancies.

Bone represents a common site of metastasis from several solid tumours, including breast, prostate and lung malignancies. The onset of bone metastases (BM) is associated not only with serious skeletal complications, but also shortened overall survival, owing to the lack of curative treatment options for late-stage cancer. Despite the diagnostic advances, BM detection often occurs in the symptomatic stage, underlining the need for novel strategies aimed at the early identification of high-risk patients. To this purpose, both bone turnover and tumour-derived markers are being investigated for their potential diagnostic, prognostic and predictive roles. In this review, we summarize the pathogenesis of BM in breast, prostate and lung tumours, while exploring the current research focused on the identification and clinical validation of BM biomarkers.

V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog A Synthetic Modified mRNA Drives Reprogramming of Human Pancreatic Duct-Derived Cells Into Insulin-Secreting Cells.

: ß-Cell replacement therapy represents the most promising approach to restore ß-cell mass and glucose homeostasis in patients with type 1 diabetes. Safety and ethical issues associated with pluripotent stem cells stimulated the search for adult progenitor cells with endocrine differentiation capacities. We have already described a model for expansion and differentiation of human pancreatic duct-derived cells (HDDCs) into insulin-producing cells. Here we show an innovative and robust in vitro system for large-scale production of ß-like cells from HDDCs using a nonintegrative RNA-based reprogramming technique. Synthetic modified RNAs for pancreatic transcription factors (pancreatic duodenal homeobox 1, neurogenin3, and V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A [MAFA]) were manufactured and daily transfected in HDDCs without strongly affecting immune response and cell viability. MAFA overexpression was efficient and sufficient to induce ß-cell differentiation of HDDCs, which acquired a broad repertoire of mature ß-cell markers while downregulating characteristic epithelial-mesenchymal transition markers. Within 7 days, MAFA-reprogrammed HDDC populations contained 37% insulin-positive cells and a proportion of endocrine cells expressing somatostatin and pancreatic polypeptide. Ultrastructure analysis of differentiated HDDCs showed both immature and mature insulin granules with light-backscattering properties. Furthermore, in vitro HDDC-derived ß cells (called ß-HDDCs) secreted human insulin and C-peptide in response to glucose, KCl, 3-isobutyl-1-methylxanthine, and tolbutamide stimulation. Transplantation of ß-HDDCs into diabetic SCID-beige mice confirmed their functional glucose-responsive insulin secretion and their capacity to mitigate hyperglycemia. Our data describe a new, reliable, and fast procedure in adult human pancreatic cells to generate clinically relevant amounts of new ß cells with potential to reverse diabetes. SIGNIFICANCE: ß-Cell replacement therapy represents the most promising approach to restore glucose homeostasis in patients with type 1 diabetes. This study shows an innovative and robust in vitro system for large-scale production of ß-like cells from human pancreatic duct-derived cells (HDDCs) using a nonintegrative RNA-based reprogramming technique. V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A overexpression was efficient and sufficient to induce ß-cell differentiation and insulin secretion from HDDCs in response to glucose stimulation, allowing the cells to mitigate hyperglycemia in diabetic SCID-beige mice. The data describe a new, reliable, and fast procedure in adult human pancreatic cells to generate clinically relevant amounts of new ß cells with the potential to reverse diabetes.

Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes.

OBJECTIVE: Although glucagon-secreting α-cells and insulin-secreting ß-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of ß-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and ß-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and ß-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and ß-cell specification and plasticity. METHODS: We sorted human α- and ß-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. RESULTS: We identified numerous transcripts with either α-cell- or ß-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to α-cells, while CHODL (chondrolectin) immunoreactivity was only present in ß-cells. Furthermore, α-cell- and ß-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. CONCLUSIONS: We have determined the genetic landscape of human α- and ß-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and ß-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.

Epidemiological Study of Child Casualties of Landmines and Unexploded Ordnances: A National Study from Iran.

BACKGROUND: Despite landmine-risk education programs and extensive demining activities on the Western border of Iran, landmines and unexploded ordnance (UXOs) still cause civilian and child casualties three decades after the Iraq-Iran war (1980-1988). The objective of this study was to understand the epidemiological patterns and risk factors of injury in child casualties of landmines and UXOs in Western and Southwestern Iran. METHODS: Children who were 18 years old or younger at the time of study and who sustained injuries from landmines and UXOs were identified through a search at the Iranian National Veterans Registry. These children participated in a 5-day gathering. The information on socioeconomic status, health-related issues, quality of life, health care utilization, and clinical profiles concerning the landmine and UXO injuries were collected. The method of data collection consisted of three component surveys: health interview, social survey, and medical examinations. Social surveys and health interviews were conducted in a face-to-face method by utilizing a questionnaire consisting of 39 questions addressing household and individual components, including information on time and type of injuries, physical activity, mental health, and quality of life. A comprehensive team of physicians in different subspecialties evaluated and examined children to assess the current medical and psychiatric conditions and physical activity, and recommended and arranged further medical, rehabilitation, or surgical planning. RESULTS: Seventy-eight child casualties were identified and participated in the study. The mean age of the participants at the time of study was 16.11 years old (SD=2 years). The mean age of victims at the time of injury was 8.2 years (SD=3.12 years; ranged from 2 to 15 years old). Sixty-seven (85.9%) of the children were male. Provinces of Kurdistan and Kermanshah had the highest number of casualties, with a total number of 54 children (68.3%). Eighty percent of the injuries were caused by landmines, and UXO explosions were reported in 20% of the cases. Overall, 24 children (30%) had received some landmine-risk education before or after the events. Sixty percent of the explosions had happened in the morning between 9:00 am and 12:00 pm. Playing and grazing livestock were the most prevalent activities/reasons at the time of injury, which were reported in 77% of the subjects. Sixty-three percent of incidents had multiple casualties and in only 13 explosions were the children the only victims of the explosion. The most prevalent injuries were amputations in 41 subjects (52.56%), followed by hearing loss in 23 subjects (29.5%). Amputations were more common in upper extremities (62%) than in lower extremities (38%). CONCLUSION: Landmines and UXOs comprise a significant safety hazard to the children living in the Western border of Iran decades after the Iraq-Iran War. The large number of injuries and lack of risk training among victims suggest that landmine cleanings and landmine-risk education should be age-specifically targeted and expanded substantially.

Epigenetic regulation in human melanoma: past and future.

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

The role of microRNAs in osteoclasts and osteoporosis.

Osteoclasts are the exclusive cells of bone resorption. Abnormally activating osteoclasts can lead to low bone mineral density, which will cause osteopenia, osteoporosis, and other bone disorders. To date, the mechanism of how osteoclast precursors differentiate into mature osteoclasts remains elusive. MicroRNAs (miRNAs) are novel regulatory factors that play an important role in numerous cellular processes, including cell differentiation and apoptosis, by post-transcriptional regulation of genes. Recently, a number of studies have revealed that miRNAs participate in bone homeostasis, including osteoclastic bone resorption, which sheds light on the mechanisms underlying osteoclast differentiation. In this review, we highlight the miRNAs involved in regulating osteoclast differentiation and bone resorption, and their roles in osteoporosis.

Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors.

Bisphosphonates (BPs) are widely used in the treatment of several bone diseases, such as osteoporosis and cancers that have metastasized to bone, by virtue of their ability to inhibit osteoclastic bone resorption. Previously, it was shown that osteoclasts present at different bone sites have different characteristics. We hypothesized that BPs could have distinct effects on different populations of osteoclasts and their precursors, for example as a result of a different capacity to endocytose the drugs. To investigate this, bone marrow cells were isolated from jaw and long bone from mice and the cells were primed to differentiate into osteoclasts with the cytokines M-CSF and RANKL. Before fusion occurred, cells were incubated with fluorescein-risedronate (FAM-RIS) for 4 or 24h and uptake was determined by flow cytometry. We found that cultures obtained from the jaw internalized 1.7 to 2.5 times more FAM-RIS than long-bone cultures, both after 4 and 24h, and accordingly jaw osteoclasts were more susceptible to inhibition of prenylation of Rap1a after treatment with BPs for 24h. Surprisingly, differences in BP uptake did not differentially affect osteoclastogenesis. This suggests that jaw osteoclast precursors are less sensitive to bisphosphonates after internalization. This was supported by the finding that gene expression of the anti-apoptotic genes Bcl-2 and Bcl-xL was higher in jaw cells than long bone cells, suggesting that the jaw cells might be more resistant to BP-induced apoptosis. Our findings suggest that bisphosphonates have distinct effects on both populations of osteoclast precursors and support previous findings that osteoclasts and precursors are bone-site specific. This study may help to provide more insights into bone-site-specific responses to bisphosphonates.

Novel polymorphisms in UTR and coding region of inducible heat shock protein 70.1 gene in tropically adapted Indian zebu cattle (Bos indicus) and riverine buffalo (Bubalus bubalis).

Due to evolutionary divergence, cattle (taurine, and indicine) and buffalo are speculated to have different responses to heat stress condition. Variation in candidate genes associated with a heat-shock response may provide an insight into the dissimilarity and suggest targets for intervention. The present work was undertaken to characterize one of the inducible heat shock protein genes promoter and coding regions in diverse breeds of Indian zebu cattle and buffaloes. The genomic DNA from a panel of 117 unrelated animals representing 14 diversified native cattle breeds and 6 buffalo breeds were utilized to determine the complete sequence and gene diversity of HSP70.1 gene. The coding region of HSP70.1 gene in Indian zebu cattle, Bos taurus and buffalo was similar in length (1,926 bp) encoding a HSP70 protein of 641 amino acids with a calculated molecular weight (Mw) of 70.26 kDa. However buffalo had a longer 5' and 3' untranslated region (UTR) of 204 and 293 nucleotides respectively, in comparison to Indian zebu cattle and Bos taurus wherein length of 5' and 3'-UTR was 172 and 286 nucleotides, respectively. The increased length of buffalo HSP70.1 gene compared to indicine and taurine gene was due to two insertions each in 5' and 3'-UTR. Comparative sequence analysis of cattle (taurine and indicine) and buffalo HSP70.1 gene revealed a total of 54 gene variations (50 SNPs and 4 INDELs) among the three species in the HSP70.1 gene. The minor allele frequencies of these nucleotide variations varied from 0.03 to 0.5 with an average of 0.26. Among the 14 B. indicus cattle breeds studied, a total of 19 polymorphic sites were identified: 4 in the 5'-UTR and 15 in the coding region (of these 2 were non-synonymous). Analysis among buffalo breeds revealed 15 SNPs throughout the gene: 6 at the 5' flanking region and 9 in the coding region. In bubaline 5'-UTR, 2 additional putative transcription factor binding sites (Elk-1 and C-Re1) were identified, other than three common sites (CP2, HSE and Pax-4) observed across all the analyzed animals. No polymorphism was found within the 3'-UTR of Indian cattle or buffalo as it was found to be monomorphic. The promoter sequences generated in 117 individuals showed a rich array of sequence elements known to be involved in transcription regulation. A total of 11 nucleotide changes were observed in the promoter sequence across the analyzed species, 3 of these changes were located within the potential transcription factor binding domains. We also identified 4 microsatellite markers within the buffalo HSP70.1 gene and 3 microsatellites within bovine HSP70.1. The present study identified several distinct changes across indicine, taurine and bubaline HSP70.1 genes that could further be evaluated as molecular markers for thermotolerance.

Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis.

Downregulation of liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and upregulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Being inhibited by its reaction product, MATII isoform upregulation cannot compensate for MATI/III decrease. Therefore, MAT1A:MAT2A switch contributes to decrease in SAM level in rodent and human hepatocarcinogenesis. SAM administration to carcinogen-treated rats prevents hepatocarcinogenesis, whereas MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular steatosis, mononuclear cell infiltration in periportal areas, and HCC development. This review focuses upon the pleiotropic changes, induced by MAT1A/MAT2A switch, associated with HCC development. Epigenetic control of MATs expression occurs at transcriptional and post-transcriptional levels. In HCC cells, MAT1A/MAT2A switch is associated with global DNA hypomethylation, decrease in DNA repair, genomic instability, and signaling deregulation including c-MYC overexpression, rise in polyamine synthesis, upregulation of RAS/ERK, IKK/NF-kB, PI3K/AKT, and LKB1/AMPK axis. Furthermore, decrease in MAT1A expression and SAM levels results in increased HCC cell proliferation, cell survival, and microvascularization. All of these changes are reversed by SAM treatment in vivo or forced MAT1A overexpression or MAT2A inhibition in cultured HCC cells. In human HCC, MAT1A:MAT2A and MATI/III:MATII ratios correlate negatively with cell proliferation and genomic instability, and positively with apoptosis and global DNA methylation. This suggests that SAM decrease and MATs deregulation represent potential therapeutic targets for HCC. Finally, MATI/III:MATII ratio strongly predicts patients' survival length suggesting that MAT1A:MAT2A expression ratio is a putative prognostic marker for human HCC.