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Article ; Online: From MASH to HCC: the role of Gas6/TAM receptors.

Apostolo, Daria / Ferreira, Luciana L / Vincenzi, Federica / Vercellino, Nicole / Minisini, Rosalba / Latini, Federico / Ferrari, Barbara / Burlone, Michela E / Pirisi, Mario / Bellan, Mattia

Frontiers in immunology

2024 Volume 15, Page(s) 1332818

Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors ... ...

Abstract	Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Liver Neoplasms ; Inflammation ; Fibrosis ; Fatty Liver
Chemical Substances	Proto-Oncogene Proteins
Language	English
Publishing date	2024-01-17
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1332818
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Article ; Online: HSD17B13 and other liver fat-modulating genes predict development of hepatocellular carcinoma among HCV-positive cirrhotics with and without viral clearance after DAA treatment.

Burlone, Michela E / Bellan, Mattia / Barbaglia, Matteo N / Mocchetti, Ginevra / Mallela, Venkata R / Minisini, Rosalba / Rigamonti, Cristina / Pirisi, Mario

Clinical journal of gastroenterology

2022 Volume 15, Issue 2, Page(s) 301–309

Abstract: Background: Genetic predisposition to accumulate liver fat (expressed by a polygenic risk score, GRS, based on the number of at-risk alleles of PNPLA3, TM6SF2, MBOAT7 and GCKR) may influence the probability of developing hepatocellular carcinoma (HCC) ... ...

Abstract	Background: Genetic predisposition to accumulate liver fat (expressed by a polygenic risk score, GRS, based on the number of at-risk alleles of PNPLA3, TM6SF2, MBOAT7 and GCKR) may influence the probability of developing hepatocellular carcinoma (HCC) after hepatitis C treatment. Whether this holds true taking into account carriage of the HSD17B13:TA splice variant, also affecting lipogenesis, and achievement of viral clearance (SVR), is unknown. Methods: PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 variants were determined in a cohort of 328 cirrhotic patients free of HCC before starting treatment with direct acting antivirals (DAA). Results: SVR in the study cohort was 96%. At the end of follow-up, N = 21 patients had been diagnosed an HCC; none of the genes included in the GRS was individually associated with HCC development. However, in a Cox proportional hazards model, a GRS > 0.457 predicted HCC independently of sex, diabetes, albumin, INR and FIB4. The fit of the model improved adding treatment outcome and carriage of the HSD17B13:TA splice variant, with sex, GRS > 0.457, HSD17B13:TA splice variant and failure to achieve an SVR (hazard ratio = 6.75, 4.24, 0.24 and 7.7, respectively) being independent predictors of HCC. Conclusion: Our findings confirm that genes modulating liver fat and lipogenesis are important risk factors for HCC development among cirrhotics C treated with DAA.
MeSH term(s)	17-Hydroxysteroid Dehydrogenases/genetics ; Antiviral Agents/therapeutic use ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Hepatitis C, Chronic/complications ; Hepatitis C, Chronic/drug therapy ; Humans ; Liver Cirrhosis/complications ; Liver Cirrhosis/drug therapy ; Liver Neoplasms/complications ; Liver Neoplasms/genetics
Chemical Substances	Antiviral Agents ; 17-Hydroxysteroid Dehydrogenases (EC 1.1.-) ; HSD17B13 protein, human (EC 1.1.-.-)
Language	English
Publishing date	2022-01-31
Publishing country	Japan
Document type	Journal Article
ZDB-ID	2429411-1
ISSN	1865-7265 ; 1865-7257
ISSN (online)	1865-7265
ISSN	1865-7257
DOI	10.1007/s12328-021-01578-1
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Article ; Online: Influence of age on sex-related differences among patients with hepatitis C.

Burlone, Michela E / Pedrinelli, Anita R / Giarda, Paola / Minisini, Rosalba / Pirisi, Mario

European journal of gastroenterology & hepatology

2016 Volume 28, Issue 9, Page(s) 1100–1101

MeSH term(s)	Hepacivirus ; Hepatitis C ; Humans ; Sex Characteristics
Language	English
Publishing date	2016
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	1034239-4
ISSN	1473-5687 ; 0954-691X
ISSN (online)	1473-5687
ISSN	0954-691X
DOI	10.1097/MEG.0000000000000668
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Zs.A 2932: Show issues

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Article: Hepatitis C virus cell entry: role of lipoproteins and cellular receptors.

Burlone, Michela E / Budkowska, Agata

The Journal of general virology

2009 Volume 90, Issue Pt 5, Page(s) 1055–1070

Abstract: Hepatitis C virus (HCV), a major cause of chronic liver disease, is a single-stranded positive sense virus of the family Flaviviridae. HCV cell entry is a multi-step process, involving several viral and cellular factors that trigger virus uptake into the ...

Abstract	Hepatitis C virus (HCV), a major cause of chronic liver disease, is a single-stranded positive sense virus of the family Flaviviridae. HCV cell entry is a multi-step process, involving several viral and cellular factors that trigger virus uptake into the hepatocyte. Tetraspanin CD81, human scavenger receptor SR-BI, and tight junction molecules Claudin-1 and occludin are the main receptors that mediate HCV entry. In addition, the virus may use glycosaminoglycans and/or low density receptors on host cells as initial attachment factors. A unique feature of HCV is the dependence of virus replication and assembly on host cell lipid metabolism. Most notably, during HCV assembly and release from the infected cells, virus particles associate with lipids and very-low-density lipoproteins. Thus, infectious virus circulates in patient sera in the form of triglyceride-rich particles. Consequently, lipoproteins and lipoprotein receptors play an essential role in virus uptake and the initiation of infection. This review summarizes the current knowledge about HCV receptors, mechanisms of HCV cell entry and the role of lipoproteins in this process.
MeSH term(s)	Hepacivirus/physiology ; Hepatitis C/virology ; Hepatocytes/virology ; Humans ; Lipoproteins/metabolism ; Models, Biological ; Receptors, Virus/metabolism
Chemical Substances	Lipoproteins ; Receptors, Virus
Language	English
Publishing date	2009-03-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/vir.0.008300-0
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Article ; Online: Direct antivirals and cognitive impairment in hepatitis C: a clinical-neurophysiologic study.

Vaghi, Gloria / Gori, Benedetta / Strigaro, Gionata / Burlone, Michela / Minisini, Rosalba / Barbaglia, Matteo N / Brigatti, Elena / Varrasi, Claudia / Pirisi, Mario / Cantello, Roberto

Journal of neurovirology

2020 Volume 26, Issue 6, Page(s) 870–879

Abstract: ... and sex, i.e., 15 patients suffering from non-alcoholic fatty liver disease (NAFLD) and 15 healthy ... some significant (p < 0.05) HCV recovery in given test domains, e.g., memory, executive functions, and reasoning ...

Abstract	Cognition was assessed in hepatitis C virus (HCV) patients, who did not meet the criteria for a minimal hepatic encephalopathy. Their liver function was compensated. We then disentangled potential cognitive changes associated with a sustained virologic response at 12 weeks (SVR-12), following treatment with direct antiviral agents (DAAs). We studied 23 selected HCV patients with a battery of standard neuropsychological tests, and with recordings of the P300 wave, a cerebral potential of "cognitive" significance. There was a baseline evaluation (T0) and a second one 6 months later (T1). We had 2 control groups of comparable age and sex, i.e., 15 patients suffering from non-alcoholic fatty liver disease (NAFLD) and 15 healthy subjects. At T0, we detected a significant (p < 0.05) cognitive impairment in the HCV group, which involved episodic and working memory, attention, visuospatial and verbal abilities, executive functions, and logic reasoning. The P300 latency was significantly (p < 0.05) delayed in the group. At T1, we observed some significant (p < 0.05) HCV recovery in given test domains, e.g., memory, executive functions, and reasoning. Accordingly, the P300 latency shortened significantly (p < 0.05). HCV patients exhibited subtle cognitive defects, somehow independent of their liver condition, possibly linked to direct or indirect brain involvement by the virus. These defects partly recovered following the SVR-12, as achieved through DAAs. The P300 wave was a valid neurophysiologic counterpart of these changes. DAAs can have a role in the early preservation of cognition in HCVs.
MeSH term(s)	Aged ; Antiviral Agents/therapeutic use ; Attention/drug effects ; Attention/physiology ; Brain/drug effects ; Brain/virology ; Case-Control Studies ; Cognition/drug effects ; Cognition/physiology ; Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/drug therapy ; Cognitive Dysfunction/psychology ; Cognitive Dysfunction/virology ; Event-Related Potentials, P300/drug effects ; Event-Related Potentials, P300/physiology ; Executive Function/drug effects ; Executive Function/physiology ; Female ; Hepacivirus/drug effects ; Hepacivirus/pathogenicity ; Hepatitis C, Chronic/diagnosis ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/psychology ; Hepatitis C, Chronic/virology ; Humans ; Liver/drug effects ; Liver/virology ; Male ; Memory, Short-Term/drug effects ; Memory, Short-Term/physiology ; Middle Aged ; Neuropsychological Tests ; Non-alcoholic Fatty Liver Disease/diagnosis ; Non-alcoholic Fatty Liver Disease/psychology ; Non-alcoholic Fatty Liver Disease/virology ; Sustained Virologic Response
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2020-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1283265-0
ISSN	1538-2443 ; 1355-0284
ISSN (online)	1538-2443
ISSN	1355-0284
DOI	10.1007/s13365-020-00904-6
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Zs.A 4426: Show issues

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Article: Identification of the Best Cut-Off Value of PIVKA-II for the Surveillance of Patients at Risk of Hepatocellular Carcinoma Development.

Caviglia, Gian Paolo / Abate, Maria Lorena / Troshina, Giulia / Carucci, Patrizia / Rolle, Emanuela / Risso, Alessandra / Burlone, Michela Emma / Albè, Alice / Crevola, Martina / Musso, Emma Clara / Rosso, Chiara / Armandi, Angelo / Olivero, Antonella / Minisini, Rosalba / Saracco, Giorgio Maria / Bugianesi, Elisabetta / Pirisi, Mario / Ciancio, Alessia / Gaia, Silvia

Biology

2023 Volume 12, Issue 1

Abstract: Patients with cirrhosis are at risk of hepatocellular carcinoma (HCC) development and, according to current guidelines, should undergo surveillance by ultrasound at six month intervals. Due to the known limitations of surveillance strategies based on ... ...

Abstract	Patients with cirrhosis are at risk of hepatocellular carcinoma (HCC) development and, according to current guidelines, should undergo surveillance by ultrasound at six month intervals. Due to the known limitations of surveillance strategies based on ultrasonography, the use of tumor biomarkers, although debated, is common practice in many centers. The aim of the study was to identify the best cut-off value for one of such biomarkers, protein induced by vitamin K absence, or antagonist-II (PIVKA-II). We retrospectively enrolled 1187 patients with liver cirrhosis: 205 with a diagnosis of HCC (median age 67 years, 81.0% males) and 982 without tumor (median age 64 years, 56.2% males). During a median follow-up (FU) of 34.6 (11.4−43.7) months, 118 out of 982 (12.0%) patients developed HCC. Serum PIVKA-II was assessed by chemiluminescence immunoassay on the Lumipulse® G600 II platform (Fujirebio, Tokyo, Japan). In the overall cohort (n = 1187), PIVKA-II showed an area under the curve (AUC) of 0.802 for HCC detection. The best cut-off value that maximized sensitivity was 50 mAU/mL (sensitivity = 80%, specificity = 64%). In the 982 patients without HCC at baseline, PIVKA-II > 50 mAU/mL was associated with an increased risk of HCC development during the FU (HR = 1.74, 95% CI 1.21−2.51; p = 0.003)). In conclusion, the evaluation of serum PIVKA-II showed a good performance for HCC detection; a cut-off value > 50 mAU/mL could be suitable for the surveillance of patients who are at risk of developing HCC.
Language	English
Publishing date	2023-01-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12010094
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Article: Liver Stiffness, Not Fat Liver Content, Predicts the Length of QTc Interval in Patients with Chronic Liver Disease.

Bellan, Mattia / Rigamonti, Cristina / Giacomini, Greta Maria / Makmur, Giulio / Marconi, Cecilia / Nicosia, Francesco / Panero, Antonio / De Benedittis, Carla / Burlone, Michela E / Minisini, Rosalba / Pirisi, Mario

Gastroenterology research and practice

2019 Volume 2019, Page(s) 6731498

Abstract: ... at discriminating steatosis from fibrosis noninvasively, i.e., transient elastography (TE) with measure of liver ...

Abstract	The severity of fatty liver at ultrasound has been associated with QT length, a finding invoked to explain the excess cardiovascular risk of patients with fatty liver. However, the ability of ultrasound to stage accurately the severity of fatty liver is limited, with fibrosis a major confounder. Here, we aimed to verify the alleged relationship between fat liver content and QT length using a technique apt at discriminating steatosis from fibrosis noninvasively, i.e., transient elastography (TE) with measure of liver stiffness (LS) and controlled attenuation parameter (CAP). A prospectively collected derivation cohort of 349 patients with chronic liver disease (CLD) of any etiology (
Language	English
Publishing date	2019-12-23
Publishing country	Egypt
Document type	Journal Article
ZDB-ID	2435460-0
ISSN	1687-630X ; 1687-6121
ISSN (online)	1687-630X
ISSN	1687-6121
DOI	10.1155/2019/6731498
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Article: Periostin Circulating Levels and Genetic Variants in Patients with Non-Alcoholic Fatty Liver Disease.

Smirne, Carlo / Mulas, Violante / Barbaglia, Matteo Nazzareno / Mallela, Venkata Ramana / Minisini, Rosalba / Barizzone, Nadia / Burlone, Michela Emma / Pirisi, Mario / Grossini, Elena

Diagnostics (Basel, Switzerland)

2020 Volume 10, Issue 12

Abstract: Circulating periostin has been suggested as a possible biomarker in non-alcoholic fatty liver disease (NAFLD) in Asian studies. In the present study, we aimed to test its still controversial relevance in a Caucasian population. In patients with ... ...

Abstract	Circulating periostin has been suggested as a possible biomarker in non-alcoholic fatty liver disease (NAFLD) in Asian studies. In the present study, we aimed to test its still controversial relevance in a Caucasian population. In patients with histologically-proven NAFLD (N. = 74; 10 with hepatocellular carcinoma, HCC) plasma periostin concentrations were analyzed. POSTN haplotype analysis was based on rs9603226, rs3829365, and rs1029728. Hepatitis C patients (N. = 81, 7 HCC) and healthy subjects (N. = 27) were used as controls. The median plasma periostin concentration was 11.6 ng/mL without differences amongst groups; it was not influenced by age, liver fibrosis or steatosis. However, possession of haplotype two (rs9603226 = G, rs3829365 = C, rs1028728 = A) was associated with lower circulating periostin compared to other haplotypes. Moreover, periostin was higher in HCC patients. At multivariate analysis, HCC remained the only predictor of high periostin. In conclusion, plasma periostin concentrations in Caucasians NAFLD patients are not influenced by the degree of liver disease, but are significantly higher in HCC. Genetically-determined differences may account for some of the variability. These data suggest extreme caution in predicting a possible future role of periostin antagonists as a rational therapeutic alternative for NAFLD, but show a potential periostin role in the management of NAFLD-associated HCC.
Language	English
Publishing date	2020-11-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics10121003
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Article ; Online: Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma.

Howell, Jessica / Atkinson, Stephen R / Pinato, David J / Knapp, Susanne / Ward, Caroline / Minisini, Rosalba / Burlone, Michela E / Leutner, Monica / Pirisi, Mario / Büttner, Reinhard / Khan, Shahid A / Thursz, Mark / Odenthal, Margarete / Sharma, Rohini

European journal of cancer (Oxford, England : 1990)

2019 Volume 116, Page(s) 56–66

Abstract: Background: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining ... ...

Abstract	Background: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. Methods: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. Results: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. Conclusion: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.
MeSH term(s)	Aged ; Biomarkers, Tumor/blood ; Biomarkers, Tumor/genetics ; Carcinoma, Hepatocellular/blood ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Circulating Tumor DNA/genetics ; Female ; Humans ; Liver Neoplasms/blood ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Male ; Middle Aged ; Mutation ; Sensitivity and Specificity
Chemical Substances	Biomarkers, Tumor ; Circulating Tumor DNA
Language	English
Publishing date	2019-06-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2019.04.014
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Zs.A 456: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 583: Show issues

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Article ; Online: B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD).

Bruzzì, Stefania / Sutti, Salvatore / Giudici, Gabriele / Burlone, Michela E / Ramavath, Naresh Naik / Toscani, Alberto / Bozzola, Cristina / Schneider, Pascal / Morello, Elisabetta / Parola, Maurizio / Pirisi, Mario / Albano, Emanuele

Free radical biology & medicine

2018 Volume 124, Page(s) 249–259

Abstract: Recent evidence implicates adaptive immunity as a key player in the mechanisms supporting hepatic inflammation during the progression of nonalcoholic fatty liver disease (NAFLD). In these settings, patients with NAFLD often show an increase in the ... ...

Abstract	Recent evidence implicates adaptive immunity as a key player in the mechanisms supporting hepatic inflammation during the progression of nonalcoholic fatty liver disease (NAFLD). In these settings, patients with NAFLD often show an increase in the circulating levels of antibodies against oxidative stress-derived epitopes (OSE). Nonetheless, the actual role of humoral immunity in NAFLD is still unclear. This study investigates the contribution of B-lymphocytes to NAFLD evolution. B-lymphocyte immunostaining of liver biopsies from NAFLD patients showed that B-cells were evident within cell aggregates rich in T-lymphocytes. In these subjects, B/T-lymphocyte infiltration positively correlated with both circulating IgG targeting oxidative stress-derived epitopes (OSE) and interferon-γ (IFN-γ) levels. Furthermore, high prevalence of lymphocyte aggregates identified patients with more severe lobular inflammation and fibrosis. In mouse models of NAFLD, the onset of steatohepatitis was characterized by hepatic B2-lymphocytes maturation to plasma cells and by an elevation in circulating anti-OSE IgG titers. B-cell responses preceded T-cell activation and were accompanied by the up-regulation in the hepatic expression of B-cell Activating Factor (BAFF). Selective B2-cell depletion in mice over-expressing a soluble form of the BAFF/APRIL receptor Transmembrane Activator and Cyclophilin Ligand Interactor (TACI-Ig) prevented plasma cell maturation and Th-1 activation of liver CD4
MeSH term(s)	Animals ; Antigens/immunology ; B-Lymphocyte Subsets/immunology ; B-Lymphocytes/immunology ; Disease Progression ; Female ; Humans ; Lymphocyte Activation/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Non-alcoholic Fatty Liver Disease/immunology ; Non-alcoholic Fatty Liver Disease/pathology ; Oxidative Stress/immunology ; T-Lymphocytes/immunology
Chemical Substances	Antigens
Language	English
Publishing date	2018-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2018.06.015
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