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1.
Front Cell Infect Microbiol ; 12: 726263, 2022.
Article in English | MEDLINE | ID: covidwho-2198679

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is resilient, highly pathogenic, and rapidly transmissible. COVID-19 patients have been reported to have underlying chronic liver abnormalities linked to hepatic dysfunction. Discussion: Viral RNAs are detectable in fecal samples by RT-PCR even after negative respiratory samples, which suggests that SARS-CoV-2 can affect the gastrointestinal tract and the liver. The case fatality rates are higher among the elderly and those with underlying comorbidities such as hypertension, diabetes, liver abnormality, and heart disease. There is insufficient research on signaling pathways. Identification of molecular mechanisms involved in SARS-CoV-2-induced damages to hepatocytes is challenging. Herein, we demonstrated the multifactorial effects of SARS-CoV-2 on liver injury such as psychological stress, immunopathogenesis, systemic inflammation, ischemia and hypoxia, drug toxicity, antibody-dependent enhancement (ADE) of infection, and several others which can significantly damage the liver. Conclusion: During the COVID-19 pandemic, it is necessary for clinicians across the globe to pay attention to SARS-CoV-2-mediated liver injury to manage the rising burden of hepatocellular carcinoma. To face the challenges during the resumption of clinical services for patients with pre-existing liver abnormalities and HCC, the impact of SARS-CoV-2 on hepatocytes should be investigated both in vitro and in vivo.


Subject(s)
COVID-19 , Carcinoma, Hepatocellular , Gastrointestinal Diseases , Liver Neoplasms , Aged , COVID-19/complications , Humans , Liver/pathology , Liver Neoplasms/pathology , Pandemics , SARS-CoV-2
2.
Front Immunol ; 13: 985781, 2022.
Article in English | MEDLINE | ID: covidwho-2022758

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a severe pandemic that has posed an unprecedented challenge to public health worldwide. Hepatocellular carcinoma (HCC) is a common digestive system malignancy, with high aggressiveness and poor prognosis. HCC patients may be vulnerable to COVID-19. Since the anti-inflammatory, immunomodulatory and antiviral effects of vitamin D, we aimed to investigate the possible therapeutic effects and underlying action mechanisms of vitamin D in COVID-19 and HCC in this study. By using a range of bioinformatics and network pharmacology analyses, we identified many COVID-19/HCC target genes and analyzed their prognostic significance in HCC patients. Further, a risk score model with good predictive performance was developed to evaluate the prognosis of HCC patients with COVID-19 based on these target genes. Moreover, we identified seven possible pharmacological targets of vitamin D against COVID-19/HCC, including HMOX1, MB, TLR4, ALB, TTR, ACTA1 and RBP4. And we revealed the biological functions, signaling pathways and TF-miRNA coregulatory network of vitamin D in COVID-19/HCC. The enrichment analysis revealed that vitamin D could help in treating COVID-19/HCC effects through regulation of immune response, epithelial structure maintenance, regulation of chemokine and cytokine production involved in immune response and anti-inflammatory action. Finally, the molecular docking analyses were performed and showed that vitamin D possessed effective binding activity in COVID-19. Overall, we revealed the possible molecular mechanisms and pharmacological targets of vitamin D for treating COVID-19/HCC for the first time. But these findings need to be further validated in actual HCC patients with COVID-19 and need further investigation to confirm.


Subject(s)
COVID-19 , Carcinoma, Hepatocellular , Liver Neoplasms , MicroRNAs , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , COVID-19/complications , COVID-19/drug therapy , Vitamin D/therapeutic use , Molecular Docking Simulation , Toll-Like Receptor 4/metabolism , Vitamins/therapeutic use , MicroRNAs/genetics , Antiviral Agents/therapeutic use , Cytokines/metabolism , Retinol-Binding Proteins, Plasma
4.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Article in English | MEDLINE | ID: covidwho-1450313

ABSTRACT

Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.


Subject(s)
Eicosanoids/metabolism , Epoxide Hydrolases/biosynthesis , Macrophages/immunology , Neoplasm Metastasis/pathology , Receptors, Prostaglandin E, EP4 Subtype/biosynthesis , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/pathology , Cell Death/drug effects , Cell Line, Tumor , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Cytokines/metabolism , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Neoplasm Metastasis/prevention & control , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Phagocytosis/immunology , RAW 264.7 Cells
5.
PLoS One ; 16(8): e0256544, 2021.
Article in English | MEDLINE | ID: covidwho-1374151

ABSTRACT

BACKGROUND: Patients with hepatocellular carcinoma (HCC) represent a vulnerable population potentially negatively affected by COVID-19-associated reallocation of healthcare resources. Here, we report the impact of COVID-19 on the management of HCC patients in a large tertiary care hospital. METHODS: We retrospectively analyzed clinical data of HCC patients who presented at the Vienna General Hospital, between 01/DEC/2019 and 30/JUN/2020. We compared patient care before (period 1) and after (period 2) implementation of COVID-19-associated healthcare restrictions on 16/MAR/2020. RESULTS: Of 126 patients, majority was male (n = 104, 83%) with a mean age of 66±11 years. Half of patients (n = 57, 45%) had impaired liver function (Child-Pugh stage B/C) and 91 (72%) had intermediate-advanced stage HCC (BCLC B-D). New treatment, was initiated in 68 (54%) patients. Number of new HCC diagnoses did not differ between the two periods (n = 14 vs. 14). While personal visits were reduced, an increase in teleconsultation was observed (period 2). Number of patients with visit delays (n = 31 (30%) vs. n = 10 (10%); p = 0.001) and imaging delays (n = 25 (25%) vs. n = 7 (7%); p = 0.001) was higher in period 2. Accordingly, a reduced number of patients was discussed in interdisciplinary tumor boards (lowest number in April (n = 24), compared to a median number of 57 patients during period 1). Median number of elective/non-elective admissions was not different between the periods. One patient contracted COVID-19 with lethal outcome. CONCLUSIONS: Changes in patient care included reduced personal contacts but increased telephone visits, and delays in diagnostic procedures. The effects on long-term outcome need to be determined.


Subject(s)
COVID-19/epidemiology , Carcinoma, Hepatocellular/diagnosis , Liver Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , COVID-19/virology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Delayed Diagnosis , Female , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Pandemics , Patients/psychology , Retrospective Studies , SARS-CoV-2/isolation & purification , Survival Rate , Telemedicine , Tertiary Care Centers
6.
Bioengineered ; 12(1): 4054-4069, 2021 12.
Article in English | MEDLINE | ID: covidwho-1348035

ABSTRACT

During the pandemic of the coronavirus disease 2019, there exist quite a few studies on angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 infection, while little is known about ACE2 in hepatocellular carcinoma (HCC). The detailed mechanism among ACE2 and HCC still remains unclear, which needs to be further investigated. In the current study with a total of 6,926 samples, ACE2 expression was downregulated in HCC compared with non-HCC samples (standardized mean difference = -0.41). With the area under the curve of summary receiver operating characteristic = 0.82, ACE2 expression showed a better ability to differentiate HCC from non-HCC. The mRNA expression of ACE2 was related to the age, alpha-fetoprotein levels and cirrhosis of HCC patients, and it was identified as a protected factor for HCC patients via Kaplan-Meier survival, Cox regression analyses. The potential molecular mechanism of ACE2 may be relevant to catabolic and cell division. In all, decreasing ACE2 expression can be seen in HCC, and its protective role for HCC patients and underlying mechanisms were explored in the study.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Carcinoma, Hepatocellular/genetics , Liver Cirrhosis/genetics , Liver Neoplasms/genetics , Neoplasm Proteins/genetics , Receptors, Virus/genetics , alpha-Fetoproteins/genetics , Age Factors , Aged , Angiotensin-Converting Enzyme 2/metabolism , Area Under Curve , COVID-19/virology , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Databases, Genetic , Datasets as Topic , Female , Gene Expression Regulation, Neoplastic , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/mortality , Liver Cirrhosis/pathology , Liver Neoplasms/diagnosis , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Proteins/classification , Neoplasm Proteins/metabolism , Protective Factors , Protein Interaction Mapping , ROC Curve , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Survival Analysis , alpha-Fetoproteins/metabolism
7.
J Formos Med Assoc ; 121(2): 454-466, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1330958

ABSTRACT

This review evaluates the ability of the fibrosis index based on four factors (FIB-4) identifying fibrosis stages, long-time prognosis in chronic liver disease, and short-time outcomes in acute liver injury. FIB-4 was accurate in predicting the absence or presence of advanced fibrosis with cut-offs of 1.0 and 2.65 for viral hepatitis B, 1.45 and 3.25 for viral hepatitis C, 1.30 (<65 years), 2.0 (≥65 years), and 2.67 for non-alcoholic fatty liver disease (NAFLD), respectively, but had a low-to-moderate accuracy in alcoholic liver disease (ALD) and autoimmune hepatitis. It performed better in excluding fibrosis, so we built an algorithm for identifying advanced fibrosis by combined methods and giving work-up and follow-up suggestions. High FIB-4 in viral hepatitis, NAFLD, and ALD was associated with significantly high hepatocellular carcinoma incidence and mortality. Additionally, FIB-4 showed the ability to predict high-risk varices with cut-offs of 2.87 and 3.91 in cirrhosis patients and predict long-term survival in hepatocellular carcinoma patients after hepatectomy. In acute liver injury caused by COVID-19, FIB-4 had a predictive value for mechanical ventilation and 30-day mortality. Finally, FIB-4 may act as a screening tool in the secondary prevention of NAFLD in the high-risk population.


Subject(s)
COVID-19 , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Fibrosis , Humans , Liver/pathology , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/pathology , SARS-CoV-2 , Severity of Illness Index
8.
Neuropeptides ; 89: 102159, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1225350

ABSTRACT

T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4+ T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1+ T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1+ T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cell Proliferation/drug effects , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Neuropeptides/pharmacology , Neurotransmitter Agents/pharmacology , Programmed Cell Death 1 Receptor/biosynthesis , Programmed Cell Death 1 Receptor/genetics , T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/metabolism , COVID-19/complications , Carcinoma, Hepatocellular/pathology , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Humans , Immunotherapy , Killer Cells, Natural/metabolism , Liver Neoplasms/pathology , Receptors, Glutamate/drug effects , Receptors, Neuropeptide/metabolism , Receptors, Neurotransmitter/metabolism
11.
Lancet Gastroenterol Hepatol ; 5(8): 765-775, 2020 08.
Article in English | MEDLINE | ID: covidwho-692971

ABSTRACT

Around the world, recommendations for cancer treatment are being adapted in real time in response to the pandemic of COVID-19. We, as a multidisciplinary team, reviewed the standard management options, according to the Barcelona Clinic Liver Cancer classification system, for hepatocellular carcinoma. We propose treatment recommendations related to COVID-19 for the different stages of hepatocellular carcinoma (ie, 0, A, B, and C), specifically in relation to surgery, locoregional therapies, and systemic therapy. We suggest potential strategies to modify risk during the pandemic and aid multidisciplinary treatment decision making. We also review the multidisciplinary management of intrahepatic cholangiocarcinoma as a potentially curable and incurable diagnosis in the setting of COVID-19.


Subject(s)
Carcinoma, Hepatocellular/therapy , Coronavirus Infections/epidemiology , Liver Neoplasms/therapy , Pandemics , Pneumonia, Viral/epidemiology , Betacoronavirus , Bile Duct Neoplasms/therapy , COVID-19 , Carcinoma, Hepatocellular/pathology , Cholangiocarcinoma/therapy , Clinical Decision-Making , Humans , Liver Neoplasms/pathology , Neoplasm Staging , Patient Care Team , Risk Factors , SARS-CoV-2
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