• 3D culture
• DILI
• HepG2
• HepaRG
• Human liver organoid
• In vitro liver model
• Pluripotent stem cell
• Primary hepatocytes

• chemokines
• crypts
• cytokeratins, keratin
• cytokines
• influenza viruses
• reticular epithelial cells
• sialic acid receptors
• squamous epithelial cells
• tonsils
• tropism

• Humans
• Epithelial Cells/virology
• Epithelial Cells/metabolism
• Epithelial Cells/immunology
• Palatine Tonsil/virology
• Palatine Tonsil/cytology
• Cytokines/metabolism
• Cytokines/genetics
• Virus Replication
• Keratins/metabolism
• Keratins/genetics
• Influenza, Human/virology
• Influenza, Human/metabolism
• Influenza, Human/immunology
• Animals
• Cell Differentiation
• Chemokines/metabolism
• Chemokines/genetics
• Receptors, Virus/metabolism
• Influenza A Virus, H1N1 Subtype
• Influenza A virus
• Cells, Cultured
• Swine
• Viral Tropism

• K99 AI166019 NIAID NIH HHS
• K99AI166019 HHS | National Institutes of Health (NIH)

• Antimicrobial activity
• Aquaculture
• Galectins
• Innate immunity

• Animals
• Crustacea/chemistry
• Crustacea/immunology
• Crustacea/metabolism
• Fishes/immunology
• Fishes/metabolism
• Galectins/metabolism
• Galectins/immunology
• Galectins/genetics
• Galectins/chemistry
• Mollusca/chemistry
• Mollusca/metabolism
• Mollusca/immunology
• Bacteria/metabolism
• Bacteria/genetics
• Anti-Infective Agents/pharmacology
• Anti-Infective Agents/metabolism
• Anti-Infective Agents/chemistry
• Immunity, Innate
• Fish Proteins/immunology
• Fish Proteins/metabolism
• Fish Proteins/chemistry
• Fish Proteins/genetics
• Humans

• Humans
• Colitis, Ulcerative/blood
• Male
• Female
• C-Reactive Protein/analysis
• Biomarkers/blood
• Adult
• Case-Control Studies
• Middle Aged
• Keratin-18/blood
• Mean Platelet Volume
• Young Adult
• Apoptosis
• Severity of Illness Index
• Peptide Fragments

• AH, Alcohol-associated hepatitis
• ALD, alcohol-associated liver disease
• ASCA, anti–Saccharomyces cerevisiae antibodies
• AUC, area under the curve
• FGF, fibroblast growth factor
• GAHS, Glasgow alcohol-associated hepatitis score
• HCC, hepatocellular carcinoma
• MELD, model for end-stage liver disease
• NASH, non-alcohol-associated steatohepatitis
• PPV, positive predictive value
• PT, prothrombin time
• VCTE, vibration-controlled transient elastography
• alcohol-associated hepatitis
• biomarkers
• cytokines
• miRNAs, MicroRNAs
• microRNA
• microbiome

• Apoptosis
• CyPA
• M30
• M65
• MPO
• NETosis
• cfDNA

• Japan Society for the Promotion of Science

• Cell biology
• Health sciences
• Pathophysiology

Fragmented cytokeratin 18 (fCK18) is released from damaged hepatocytes undergoing apoptosis and is recognized as a liver condition biomarker. We have developed a highly sensitive serum fCK18 CLEIA and reported that serum levels of this caspase-derived protein were significantly associated with hepatocyte ballooning, thus assisting in the accurate diagnosis of nonalcoholic steatohepatitis (NASH). We aim to investigate serum fCK18 levels in a variety of chronic liver diseases and to explore its potential as a prognostic marker of survival in hepatocellular carcinoma (HCC) patients.

Serum fCK18 levels were measured using a highly sensitive CLEIA in 497 chronic liver disease patients (297 outpatients and 200 hospitalized with HCC).

In 497 chronic liver disease patients, serum fCK18 levels were significantly correlated with overall liver condition, including ALT, FIB-4 index and albumin-bilirubin (ALBI) score and were significantly increased in patients with HCC. In 200 HCC patients, serum fCK18 levels were significantly correlated with alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), and were significantly associated with HCC stage, whereas FIB-4 index and ALBI score were not changed based on HCC stage. The Survival group had significantly lower levels of serum fCK18, AFP, DCP, FIB-4 index and ALBI score. A ROC analysis yield area under the curve (AUC) value of 0.728 for serum fCK18 is a significantly high value when compared to AUC measurements for other factors. Notably, AUROC values for serum fCK18 levels were constant in the short- and long-term by time-dependent ROC analysis for the prediction of HCC patient survival. HCC patients with serum fCK18 measured at < 1.15 ng/mL, AFP < 7.7 ng/mL, DCP < 133 mAU/mL, ALBI score < -2.97 or FIB-4 index < 6.4 had significantly longer rates of survival when compared to patients with values exceeding these thresholds. Serum fCK18 (HR, 3.5; P < 0.0001), DCP (HR, 3.2; P < 0.0001) and Barcelona Clinic Liver Cancer (BCLC) (HR, 2.4; P = 0.001) values were independent predictors of patient survival. [Conclusion] Serum fCK18 levels reflect overall liver function, the level of liver fibrosis and the progression of HCC, and are a potential predictor of survival in HCC patients.

• Japan Society for the Promotion of Science
• Japan Agency for Medical Research and Development

Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opportunities exist to rehabilitate organ function with adjunct therapeutics during normothermic machine perfusion. In this preclinical study, we targeted the apoptosis pathway as a potential method of improving hepatocellular function. Treatment of discarded human livers during normothermic perfusion with an irreversible pan-caspase inhibitor, emricasan, resulted in significant mitigation of innate immune and pro-inflammatory responses at both the transcriptional and protein level. This was evidenced by significantly decreased circulating levels of the pro-inflammatory cytokines, interleukin-6, interleukin-8, and interferon-gamma, compared to control livers. Compared to emricasan-treated livers, untreated livers demonstrated transcriptional changes notable for enrichment in pathways involved in innate immunity, leukocyte migration, and cytokine-mediated signaling. Targeting of unregulated apoptosis may represent a viable therapeutic intervention for immunomodulation during machine perfusion.

• Caspases/metabolism
• Humans
• Immunity, Innate
• Liver/metabolism
• Liver Transplantation/methods
• Organ Preservation/methods
• Perfusion/methods

• T32 ES007272 NIEHS NIH HHS
• R01 DK114506 NIDDK NIH HHS
• R01 DK107875 NIDDK NIH HHS
• R01 DK096075 NIDDK NIH HHS
• National Institute of Diabetes and Digestive and Kidney Diseases
• Division of Engineering Education and Centers
• Massachusetts General Hospital
• National Institute of Environmental Health Sciences

• KRT18
• apoptosis
• colon cancer
• miR-186-3p
• proliferation
• viability

• Animals
• Apoptosis/genetics
• Cell Line, Tumor
• Cell Proliferation/genetics
• Colonic Neoplasms/genetics
• Humans
• Mice
• MicroRNAs/metabolism
• Signal Transduction/genetics

• centrifugation
• drug-induced liver injury
• immunoassay
• mass spectrometry
• plasma
• preanalytical effects
• serum
• serum gel

• Biomarker
• Cytokeratin-18 (CK18)
• Drug-induced liver injury (DILI)
• Hepatotoxicity
• In vivo

• Biomarkers/blood
• Chemical and Drug Induced Liver Injury/blood
• Chemical and Drug Induced Liver Injury/diagnosis
• Humans
• Keratin-18/blood
• Liver/drug effects
• Liver/enzymology

• Merck

• Lactobacillus casei
• SeNps
• apoptosis
• biogenic nanoparticles
• colon cancer
• immunogenic cell death
• selenium nanoparticles

• MIS 5050556 Operational. programme: Human Resources Development, Educcation and Lifelong learning 2014-2020

Fragmented cytokeratin 18 (fCK18) released from epithelial cells undergoing apoptosis is widely studied in various diseases. However, fCK18 measurement is not utilized in clinical practice due to imprecise disease-state cutoff values. Therefore, we set out to generate new monoclonal antibodies (mAbs) and a recombinant fCK18 (rfCK18) calibrator in an effort to develop a highly sensitive chemiluminescent enzyme immunoassay (CLEIA). New capture mAb (K18-624) had a high binding ability compared to the current commercial antibody. New detection mAb (K18-328) recognized 323S-340G of CK18. A rfCK18 was expressed in the soluble fraction of E. coli when the N-terminal region (260 amino acid residues) of CK18 was truncated. Analysis of performance and measurement of human fCK18 were evaluated using K18-624 and K18-328 in a highly sensitive CLEIA. The coefficients of variation (CV) for within-run and between-day repeatability were below 10% and the recoveries were in the range of 15%. The detection sensitivity was 0.056 ng/mL. Serum fCK18 levels were significantly increased in non-alcoholic steatohepatitis (NASH) patients when compared to healthy individuals. Our new fCK18 mAbs showed high affinity and sensitivity. CLEIA using our new antibodies will be useful in measuring fCK18 in human blood thereby generating accurate clinical diagnoses of human liver diseases.

• Alcoholic hepatitis
• Biomarker
• Cytokines
• Extracellular vesicles
• Fibrosis
• Maddrey’s
• Microbiome
• microRNA

The study aim was to determine the benefit of the measurement of serum caspase-cleaved cytokeratin-18 (CK-18) fragment as a prognostic marker of febrile neutropenia (FN) in hematological patients. The study population consisted of 86 consecutive patients with FN who received intensive chemotherapy for hematological malignancy at the adult hematology ward of Kuopio University Hospital. Twenty-three patients (27%) had acute myeloid leukemia, and 63 patients (73%) were autologous stem cell transplant recipients. Serum caspase-cleaved CK-18 fragment M30, C-reactive protein (CRP) and procalcitonin (PCT) were measured at the onset of FN (d0), on day 1 (d1), and on day 2 (d2). Eight patients (9%) developed severe sepsis, including three patients with septic shock. Eighteen patients (21%) had a blood culture-positive infection. Serum CK-18 fragment peaked on the first day after fever onset in patients with severe sepsis. Higher CK-18 level was associated with severe sepsis, intensive care unit treatment, and fatal outcome, but not with blood culture positivity. In ROC curve analysis, d1 serum CK-18 fragment predicted severe sepsis with an area under the curve (AUC) of 0.767, CRP with an AUC of 0.764, and PCT with an AUC of 0.731. On d2, the best predictive capacity was observed for CRP with an AUC of 0.832. The optimal cutoff of caspase-cleaved CK-18 fragment M30 for predicting severe sepsis was 205 U/L on d1. In hematological patients, serum CK-18 fragment was found to be a potential prognostic marker of severe sepsis at early stages of FN.

• Acute myeloid leukemia
• Caspase-cleaved cytokeratin-18
• Febrile neutropenia
• Non-Hodgkin lymphoma
• Procalcitonin
• Severe sepsis

• KRT18
• RNA-Seq
• alternative splicing
• cell cycle and apoptosis
• gastric cancer

• Keratin-18
• M65
• adolescents
• apoptosis
• ethanol

• Adolescent
• Alanine Transaminase/blood
• Alcoholic Intoxication/blood
• Alcoholic Intoxication/physiopathology
• Apoptosis
• Aspartate Aminotransferases/blood
• Biomarkers/blood
• Chemical and Drug Induced Liver Injury/blood
• Chemical and Drug Induced Liver Injury/diagnosis
• Enzyme-Linked Immunosorbent Assay
• Female
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Humans
• Keratin-18/analysis
• Keratin-18/blood
• Male
• Peptide Fragments/blood
• Poland
• Preliminary Data
• Prospective Studies
• ROC Curve
• Underage Drinking

Colon cancer is the second leading cause of cancer-related mortality worldwide, and the prognosis of advanced colon cancer has remained poor in recent years. Galectin-9 (Gal-9) is a tandem-repeat type galectin that has recently been shown to exert antiproliferative effects on various types of cancer cells. The present study aimed to assess the effects of Gal-9 on human colon and colorectal cancer cells in vitro and in vivo, as well as to evaluate the microRNAs (miRNAs/miRs) associated with the antitumor effects of Gal-9. We examined the ability of Gal-9 to inhibit cell proliferation via apoptosis, and the effects of Gal-9 on cell cycle-related molecules in various human colon and colorectal cancer cell lines. In addition, Gal-9-mediated changes in activated tyrosine kinase receptors and angiogenic molecules were assessed using protein array chips in colon and colorectal cancer cells. Moreover, miRNA array analysis was performed to examine Gal-9-induced miRNA expression profiles. We also elucidated if Gal-9 inhibited tumor growth in a murine in vivo model. We found that Gal-9 suppressed the cell proliferation of colon cancer cell lines in vitro and in vivo. Our data further revealed that Gal-9 increased caspase-cleaved keratin 18 levels in Gal-9-treated colon cancer cells. In addition, Gal-9 enhanced the phosphorylation of ALK, DDR1, and EphA10 proteins. Furthermore, the miRNA expression levels, such as miR-1246, miR-15b-5p, and miR-1237, were markedly altered by Gal-9 treatment in vitro and in vivo. In conclusion, Gal-9 suppresses the cell proliferation of human colon cancer by inducing apoptosis, and these findings suggest that Gal-9 can be a potential therapeutic target in the treatment of colon cancer.

• apoptosis
• caspase‑cleaved keratin 18
• colon cancer
• galectin‑9
• microRNAs

Cisplatin remains an integral part of the treatment for muscle invasive bladder cancer. A large number of patients do not respond to cisplatin-based chemotherapy and efficacious salvage regimens are limited. Immunotherapy has offered a second line of treatment; however, only approximately 20% of patients respond, and molecular subtyping of tumors indicates there may be significant overlap in those patients that respond to cisplatin and those patients that respond to immunotherapy. As such, restoring sensitivity to cisplatin remains a major hurdle to improving patient care. One potential source of compounds for enhancing cisplatin is naturally derived bioactive products such as phytochemicals, flavonoids and others. These compounds can activate a diverse array of different pathways, many of which can directly promote or inhibit cisplatin sensitivity. The purpose of this review is to understand current drug development in the area of natural products and to assess how these compounds may enhance cisplatin treatment in bladder cancer patients.

• Cisplatin
• apoptosis
• bladder cancer
• natural products

• biomarkers
• clinical application
• detecting methods
• guidelines
• regulated cell death

• emricasan
• liver cirrhosis
• liver fibrosis
• caspase
• hepatic function

• End Stage Liver Disease
• Fibrosis
• Humans
• Liver Cirrhosis/drug therapy
• Pentanoic Acids
• Severity of Illness Index

Under normal conditions, adult hepatocytes express only keratin-8 (K8) and keratin-18 (K18), whereas cholangiocytes also express K19. In this study, we delineate the pattern of normal time-course changes in serum K19 and K18 levels after liver transplantation. Patients and Methods. Serum levels of the K19 fragment CYFRA 21-1 and the K18 fragments tissue polypeptide specific antigen (TPS) and M30 (a neoepitope that is generated after caspase cleavage during apoptosis) were measured at baseline and at regular intervals (up to 6 months) after liver transplantation in 11 adult patients.

There was a gradual decrease in serum K19 concentrations from baseline values after transplantation, following a time-course pattern similar to that of serum bilirubin. In contrast, serum concentrations of K18 fragments increased markedly shortly after transplantation and gradually decreased thereafter, following a time-course pattern similar to that of serum transaminases. The increase in TPS tended to occur earlier than that in M30, suggesting an initial predominance of hepatocyte necrosis followed by a predominance of apoptosis in the first days after transplantation. Five patients presented posttransplant complications (acute rejection in three cases and HCV recurrence in two cases). An early increase in serum K19 concentrations was observed in all cases. An increase in serum concentrations of K18 fragments (M30 and TPS) was observed in the two cases with HCV recurrence and was more variable in the three cases with acute rejection.

Serum concentrations of K19 and K18 fragments follow a dissimilar pattern of time-course changes after liver transplantation. The diagnostic value of variations in these normal patterns should be addressed in future studies.

• cancer
• cytokeratin 18
• monoclonal antibody

• diagnostic test
• liver fibrosis
• noninvasive biomarkers

• UL1 TR002649 NCATS NIH HHS
• Center for Clinical and Translational Research

• Bcl-2 proteins
• Chemotherapy
• Ovarian cancer
• RAB25

• Cardiovascular
• Cytokeratin 18
• Hemodialysis
• Probiotic
• Synbiotic

• Colorectal cancer
• inflammation
• keratin 18
• necrosis
• survival

• Caspase 3/7
• Cleaved keratin-18 (cCK18)
• Emricasan
• Full-length keratin-18 (flCK18)
• Liver fibrosis
• Non-alcoholic steatohepatitis

• Adolescent
• Adult
• Aged
• Alanine Transaminase/blood
• Biopsy
• Caspase Inhibitors/administration & dosage
• Double-Blind Method
• Female
• Hepatocytes/pathology
• Humans
• Liver/pathology
• Liver Cirrhosis/blood
• Liver Cirrhosis/complications
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/pathology
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease/blood
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/pathology
• Odds Ratio
• Pentanoic Acids/administration & dosage
• Treatment Outcome
• Young Adult

Computed tomography (CT) scans are the gold standard to measure treatment success of non-small cell lung cancer (NSCLC) therapies. Here, we investigated the very early tumor response of patients receiving chemotherapy or targeted therapies using a panel of already established and explorative liquid biomarkers. Blood samples from 50 patients were taken at baseline and at three early time points after therapy initiation. DNA mutations, a panel of 17 microRNAs, glycodelin, glutathione disulfide, glutathione, soluble caspase-cleaved cytokeratin 18 (M30 antigen), and soluble cytokeratin 18 (M65 antigen) were measured in serum and plasma samples. Baseline and first follow-up CT scans were evaluated and correlated with biomarker data. The detection rate of the individual biomarkers was between 56% and 100%. While only keratin 18 correlated with the tumor load at baseline, we found several individual markers correlating with the tumor response to treatment for each of the three time points of blood draws. A combination of the five best markers at each time point resulted in highly significant marker panels indicating therapeutic response (R² = 0.78, R² = 0.71, and R² = 0.71). Our study demonstrates that an early measurement of biomarkers immediately after therapy start can assess tumor response to treatment and might support an adaptation of treatment to improve patients’ outcome.

• NSCLC
• chemotherapy
• early response biomarkers
• liquid biomarkers
• targeted therapy

To investigate the efficacy of evaluating prognosis and response to lung cancer treatment using M30 and M65 antigens, which are indicators of necrosis.

Forty-eightpatients with lung cancer, who were planned to receive neoadjuvant chemotherapy, and 38 healthy volunteers were enrolled in the study. Using M30 and M65 levels, cytokeratin 18 levels were measured twice: before and 48 hours after the first chemotherapy treatment. Apoptotic and total necrosis levels were determined by measuring the M65 and M30 levels.

The M30 and M65 antigen levels in the patient group were significantly higher than in the control group (p< 0.001). The M30 and M65 antigen levels were significantly higher 48 hours after the chemotherapy compared with before the chemotherapy (p< 0.001). There were no significant differences in M65 levels between patients who responded to treatment and patients who progressed. The M30 levels increased significantly in patients with disease progression (p= 0.694 and p = 0.024, respectively). No significant differences in serum M30 and M65 antigen levels were found when compared between the surviving and deceased patients (p = 0.126 and p = 0.340, respectively).

A significant increase was detected in serum M30 and M65 levels in patients with lung cancer. There was a greater increase in serum M30 levels in patients who did not respond to the chemotherapy. This result gives rise to the thought that evaluating apoptosis and total necrosis through M30 and M65 measurements alone only in patients receiving neoadjuvant chemotherapy would be insufficient for specifying the effectiveness of the treatment.

• cytokeratin
• lung cancer
• neoadjuvant treatment
• prognosis

• Apoptosis
• Biomarker
• Cell death
• Necroptosis
• Necrosis

Background: Gastrointestinal cancer is one of the most common neoplasms. Cytokeratin 18(CK18) is widely expressed in many different organs and cancers. Emerging data suggested conflicting results about the role of CK18 during carcinogenesis. The aim of this study is to systematically review the prognostic value of circulating CK18 (M65) and caspase-Cleaved CK18 (M30) in digestive cancers.

Materials and Methods: We searched major database for manuscripts reporting the effect of pretreatment CK18 on survival of digestive cancer patients. Revman5.3 and R were the software used for analysis. Pooled multivariable-adjusted hazard ratios (HR) for overall survival (OS) were calculated in all patients and many different subgroup analyses by stratifying on tumor type, metastasis stage, and ethnicity.

Results: 11 original studies were included for analysis. A low level of M30 and M65 were shown to be a protective factor for all cancer patients (HR 0.49, 95%CI 0.33-0.73, P=0.0003; HR 0.48, 95% CI 0.32-0.70, P =0.0001, respectively). The low M30 remained to be a protective factor for metastasized cancer patients while M65 had no statistically significant correlation with prognosis.

Conclusions: Non-invasive total and cleaved CK18 level detection by ELISA could be potentially a useful predictor of prognosis of digestive cancer patients. Further studies are warranted to investigate the molecular mechanisms of CK18.

• Cancer
• Cytokeratins
• Prognosis

Noninvasive markers of liver fibrosis in alcoholic liver disease (ALD) are crucial to establish early intervention. Previous studies have suggested that plasma levels of cleaved keratin-18 (K18; M30) fragments can predict the severity of liver disease. The aim of this study was to correlate plasma M30 levels with stages of liver fibrosis in ALD.

Patients with ALD (n=139, 79.1% males) and liver histology were included, and plasma samples were collected to quantify plasma M30 levels. Patients were stratified into five groups by fibrosis stage (F0=14; F1=15; F2=35; F3=17; and F4=58) according to the Kleiner score. Differences between groups were evaluated using the chi-square test or analysis of variance. Trends by fibrosis stage were calculated by logistic regression analysis, and sensitivity, specificity and positive and negative predictive values were determined.

There were no significant differences in M30 levels among fibrosis stages. The correlation between plasma M30 levels and fibrosis was poor (Pearson’s correlation coefficient=0.13, Spearman rho=0.20 [p=0.02]), and M30 levels did not correlate with alcohol-specific histological features. However, significant correlations of M30 levels with aspartate aminotransferase (Spearman rho=0.653, p<0.001) and alanine aminotransferase (Spearman rho=0.432, p<0.001) were found. M30 levels of >200 U/L reveal a sensitivity for predicting cirrhosis of 84.5% with a negative predictive value of 73.5%.

Plasma M30 levels are often elevated in ALD and correlate with serum transaminases but do not reflect fibrosis. The usefulness as a prognostic marker awaits evaluation in prospective studies.

• Apoptosis
• Caspases
• Fibrosis progression
• Noninvasive diagnosis

• animal model
• critical care
• lung
• oxidative stress
• peritoneum
• trauma

Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.

• LC3
• M30
• TUNEL
• apoptosis
• autophagy
• beclin 1
• chemoendocrine therapy
• endocrine therapy
• metronomic

• Cytokeratin 18
• Liver pathological severity
• Nonalcoholic fatty liver
• Routine clinico-biological indices