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Khanal R, Heinen N, Bogomolova A, Meister TL, Herrmann ST, Westhoven S, Nocke MK, Todt D, Jockenhövel F, Klein IM, Hartmann L, Vondran FWR, Steinmann E, Zimmer G, Ott M, Brown RJP, Sharma AD, Pfaender S. MicroRNAs modulate SARS-CoV-2 infection of primary human hepatocytes by regulating the entry factors ACE2 and TMPRSS2. Liver Int 2024; 44:2983-2995. [PMID: 39175256 DOI: 10.1111/liv.16079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 08/10/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND AND AIMS Severe acute respiratory syndrome coronavirus (SARS-CoV-2) preferentially infects the respiratory tract; however, several studies have implicated a multi-organ involvement. Hepatic dysfunctions caused by SARS-CoV-2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non-coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection. METHODS We analysed liver autopsies from a coronavirus disease 19 (COVID-19)-positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS-CoV-2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT-PCRs, western blots and luciferase reporter assays were performed. RESULTS We could detect SARS-CoV-2 RNA in COVID-19-positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS-CoV-2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS-CoV-2 receptor expression and SARS-CoV-2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR-141-3p to the SARS-CoV-2 genome. CONCLUSION We confirm that PHH are susceptible to SARS-CoV-2 infection and demonstrate selected miRNAs targeting SARS-CoV-2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS-CoV-2 and associated dysfunctions in COVID-19.
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Affiliation(s)
- Rajendra Khanal
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group Liver Regeneration & RNA Therapeutics, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Natalie Heinen
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Alexandra Bogomolova
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group Liver Regeneration & RNA Therapeutics, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Toni L Meister
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Institute for Infection Research and Vaccine Development (IIRVD), Centre for Internal Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Simon T Herrmann
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
| | - Saskia Westhoven
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
| | - Maximilian K Nocke
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Daniel Todt
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Freya Jockenhövel
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Isabel M Klein
- Tissue Bank of the German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Laura Hartmann
- Tissue Bank of the German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Florian W R Vondran
- Department of General, Visceral, Pediatric and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Eike Steinmann
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Gert Zimmer
- Institute of Virology and Immunology, Bern, Switzerland
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Michael Ott
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard J P Brown
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Amar Deep Sharma
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group Liver Regeneration & RNA Therapeutics, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Stephanie Pfaender
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
- University of Lübeck, Lübeck, Germany
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Guo Y, Shen B, Lou C, Wang L, Li Y. IGSF1: a biomarker for predicting prognosis, immunotherapy response, and drug candidates in COVID-19 combined hepatocellular carcinoma. Discov Oncol 2024; 15:599. [PMID: 39470901 PMCID: PMC11522225 DOI: 10.1007/s12672-024-01483-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 10/22/2024] [Indexed: 11/01/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with poor prognosis and a common cause of cancer-related death worldwide, and despite ongoing therapeutic breakthroughs, patient survival benefits are limited. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19) and poses a major threat to humanity worldwide. As the epidemic continues to develop, more and more people are infected with SARS-CoV-2, including patients with HCC. However, the relationship between COVID-19 and HCC has not yet been fully elucidated. Our study aimed to identify the shared genetic characteristics and molecular mechanisms between COVID-19 and HCC. The data involved in this study come from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression(GTEx), and Cancer Cell Line Encyclopedia(CCLE) databases. We used differentially expressed genes to perform enrichment analysis to reveal the biological landscape of COVID-19 combined with HCC. In addition, weighted gene co-expression network analysis (WGCNA) was used to study the co-expression network related to COVID-19 and HCC. We then combined the validation datasets to screen out immunoglobulin superfamily member 1 (IGSF1) as the most important core gene. Finally, we extensively studied the functional expression of IGSF1 in tumor samples, normal tissues, and cancer cell lines. The molecular mechanisms related to COVID-19 and HCC are rarely studied. Our study identifies IGSF1 as a potential therapeutic target and immune-related biomarker for patients with COVID-19 and HCC.
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Affiliation(s)
- Yuanhui Guo
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Baixuan Shen
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Chaoxuan Lou
- Department of Pharmacy, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Li Wang
- Department of Pharmacy, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Ying Li
- Department of Pharmacy, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.
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Challa SR, Oskrochi G, Singh GP, Chirumamilla LG, Shayegh N, Nair VK, Littleton M, Byer DT, Morrison NA, Grossi BL, Ashanna B, Dusmatova S, Thompson T, Dawodu DO, Brim H, Ashktorab H. Predictors of mortality in hospitalized African American COVID-19 patients with cancer. Transl Cancer Res 2024; 13:1314-1322. [PMID: 38617523 PMCID: PMC11009794 DOI: 10.21037/tcr-23-166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 10/29/2023] [Indexed: 04/16/2024]
Abstract
Background Coronavirus disease 2019 (COVID-19) manifest differently depending on patients' background and pre-existing conditions. It remains unclear how African Americans with cancer have been affected in comparison to those without. In this study, we aim to identify demographic, clinical, and laboratory markers associated with mortality in COVID-19 patients with cancer. Methods We reviewed all COVID-19 hospitalized patients' records from Dec. 2019 to Oct. 2021 at Howard University Hospital. Patients having a history of, or active, cancer were reviewed. Clinical, treatment, lab test values, and pathological data were extracted. Univariable and multivariable analyses were conducted on the entire cohort as well as on cases and controls separately, using SPSS software. Results Out of 512 COVID-19 infected patients, 49 had cancer, either active or history of cancer (cases) and 463 COVID-19 were cancer-free (controls), allowing for comparison. African American race was predominant in both cases and controls, 83.7% and 66.7% respectively. Cancer patients were older than non-cancer patients (mean age: 70.6 vs. 56.3 years) and had an increased length of hospital stay (mean 13.9 vs. 9.4 days). Mortality is significantly higher among cancer patients (n=10, 20.4%, P=0.03) compared to non-cancer COVID-19 patients (n=41, 8.9%). Among cancer patients, breast cancer was more prevalent in females and prostate cancer in males (54% and 52%, respectively). A comparison of patients with active vs. previous cancer showed no significant difference in the clinical outcome, death vs. discharge (P=0.34). A higher reduction in albumin level in cancer cases, from the time of admission to day 5, was significantly associated with death during the hospital stay compared to those discharged (n=24, 49.0%, P<0.001). In controls, lymphopenia (n=436, 94.2%, P=0.05), aspartate aminotransferase (AST) (n=59, 12.7%, P=0.008) and albumin (n=40, 8.6%, P=0.02) have shown an association with increased mortality. Conclusions Albumin level has an inverse relationship with clinical outcomes among all COVID-19 infected cancer patients. Reduction in albumin level during the hospital stay, particularly in COVID-19 cancer patients should be considered as a predictor of mortality. Further research with a large cohort size is needed to verify and identify other predictors of outcomes in COVID-19 patients with cancer.
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Affiliation(s)
| | - Gholamreza Oskrochi
- College of Engineering and Technology, American University of the Middle East, Egalia, Kuwait
| | - Gagan Paul Singh
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Lakshmi G. Chirumamilla
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Nader Shayegh
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Vaisakh K. Nair
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Megan Littleton
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Danae T. Byer
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Nicole A. Morrison
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Brittany L. Grossi
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Barclay Ashanna
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Shahnoza Dusmatova
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Trae Thompson
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Dideolu O. Dawodu
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Hassan Brim
- Department of Pathology and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
| | - Hassan Ashktorab
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington, DC, USA
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Odintsova AK, Akberova DR, Sadykova LR, Cheremina NA, Minnullin MM, Kirshin AA, Gabitova EN, Khasanshina AY, Abdulganieva DI. Thirteen-Year Follow-Up of a Patient with Liver Cirrhosis Resulting from the Overlap Syndrome of Autoimmune Hepatitis and Primary Biliary Cholangitis: Severe COVID-19 and Liver Transplantation. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:76-84. [DOI: 10.22416/1382-4376-2024-34-1-76-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Aim: to present the difficulties of long-term management of a patient with liver cirrhosis in the outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis) who suffered from severe COVID-19 infection.Key points. The diagnosis of liver cirrhosis as an outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis) was established at the patient’s age of 33 years. At the age of 40, the patient became pregnant for the first time, the pregnancy proceeded well, and a cesarean section was performed at 36 weeks. At the age of 45, the patient suffered a severe new coronavirus infection, followed by decompensation of liver cirrhosis, which required liver transplantation 4 months after COVID-19, followed by a favorable postoperative course.Conclusion. This clinical case demonstrates the successful onset and outcome of pregnancy in a patient with liver cirrhosis in the outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis). The pronounced activity of the disease after severe new coronavirus infection required liver transplantation with successful outcome.
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Affiliation(s)
- A. Kh. Odintsova
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | | | - L. R. Sadykova
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | - N. A. Cheremina
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | | | - A. A. Kirshin
- Republican Clinical Oncological Dispensary named after Professor M.Z. Sigal
| | - E. N. Gabitova
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | - A. Yu. Khasanshina
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | - D. I. Abdulganieva
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan; Kazan State Medical University
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Ismailova AG, Maslennikov RV, Zharkova MS, Ivashkin VT. Impact of Novel Coronavirus Infection on the Course and Prognosis of Cirrhosis. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 33:65-80. [DOI: 10.22416/1382-4376-2023-33-6-65-80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
Аim: to investigate the impact of COVID-19 on the course and prognosis of cirrhosis.Materials and methods. This was a cohort study in patients with cirrhosis. We included patients with cirrhosis who underwent a medical examination at our center between September 2019 and March 2020. We determined which of these patients were infected with COVID-19, died of COVID-19, or died of cirrhosis complications within the follow-up period from April 2020 to September 2021. Thereafter, we conducted a second medical examination of these surviving patients with cirrhosis in September to December 2021.Results. Among the 226 patients included in the study, 57 had COVID-19, among which 19 patients who died of the disease. Acute-on-chronic liver failure (ACLF) developed in 16 (28.1 %) patients with cirrhosis and COVID-19, 13 (81.3 %) of whom died. One of the COVID-19 survivors eventually died of liver decompensation. Twenty patients who did not have COVID-19 died of complications of cirrhosis (ACLF) during the follow-up period. The mortality rate in patients who were infected with COVID-19 was higher than that in patients who were not infected (35.1 % vs. 14.2 %; p = 0.001). COVID-19 was an independent risk factor for death in patients with cirrhosis. No liver-specific factors predisposing to COVID-19 infection were identified. A more impaired liver function in the pre-pandemic medical examination was a predisposing factor for death in patients who had COVID-19. Patients who died of COVID-19 had better liver function in the pre-pandemic medical examination than patients without COVID-19 who died of complications of cirrhosis during the follow-up period. The liver-related mortality rate and the incidence of liver decompensation or bleeding from esophageal varices during the follow-up period were not significantly different between patients who recovered from COVID-19 and patients with cirrhosis who did not have COVID-19. Among the analyzed survivors, no significant changes were found in the main indicators of liver function after the follow-up period between patients with and without COVID-19, except for the prothrombin index, which was higher in patients after COVID-19.Conclusion. COVID-19 worsens the prognosis of patients with cirrhosis but does not substantially affect the course of cirrhosis after the recovery from this infection.
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Affiliation(s)
- A. G. Ismailova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - R. V. Maslennikov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - M. S. Zharkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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Zou J, Li J, Zhong X, Tang D, Fan X, Chen R. Liver in infections: a single-cell and spatial transcriptomics perspective. J Biomed Sci 2023; 30:53. [PMID: 37430371 PMCID: PMC10332047 DOI: 10.1186/s12929-023-00945-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/27/2023] [Indexed: 07/12/2023] Open
Abstract
The liver is an immune organ that plays a vital role in the detection, capture, and clearance of pathogens and foreign antigens that invade the human body. During acute and chronic infections, the liver transforms from a tolerant to an active immune state. The defence mechanism of the liver mainly depends on a complicated network of intrahepatic and translocated immune cells and non-immune cells. Therefore, a comprehensive liver cell atlas in both healthy and diseased states is needed for new therapeutic target development and disease intervention improvement. With the development of high-throughput single-cell technology, we can now decipher heterogeneity, differentiation, and intercellular communication at the single-cell level in sophisticated organs and complicated diseases. In this concise review, we aimed to summarise the advancement of emerging high-throughput single-cell technologies and re-define our understanding of liver function towards infections, including hepatitis B virus, hepatitis C virus, Plasmodium, schistosomiasis, endotoxemia, and corona virus disease 2019 (COVID-19). We also unravel previously unknown pathogenic pathways and disease mechanisms for the development of new therapeutic targets. As high-throughput single-cell technologies mature, their integration into spatial transcriptomics, multiomics, and clinical data analysis will aid in patient stratification and in developing effective treatment plans for patients with or without liver injury due to infectious diseases.
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Affiliation(s)
- Ju Zou
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jie Li
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiao Zhong
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Xuegong Fan
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Ruochan Chen
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Mangoni AA, Zinellu A. An Updated Systematic Review and Meta-Analysis of the Association between the De Ritis Ratio and Disease Severity and Mortality in Patients with COVID-19. Life (Basel) 2023; 13:1324. [PMID: 37374107 DOI: 10.3390/life13061324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Patients with Coronavirus disease 2019 (COVID-19) often have elevations in markers of liver injury, particularly serum aspartate transaminase (AST) and alanine transaminase (ALT). Such alterations may affect the AST/ALT ratio (De Ritis ratio) and, potentially, clinical outcomes. We conducted an updated systematic review and meta-analysis of the association between the De Ritis ratio and COVID-19 severity and mortality in hospitalized patients. PubMed, Web of Science, and Scopus were searched between 1 December 2019 and 15 February 2023. The Joanna Briggs Institute Critical Appraisal Checklist and the Grading of Recommendations, Assessment, Development, and Evaluation were used to assess the risk of bias and the certainty of the evidence, respectively. Twenty-four studies were identified. The De Ritis ratio on admission was significantly higher in patients with severe disease and non-survivors vs. patients with non-severe disease and survivors (15 studies, weighted mean difference = 0.36, 95% CI 0.24 to 0.49, p < 0.001). The De Ritis ratio was also associated with severe disease and/or mortality using odds ratios (1.83, 95% CI 1.40 to 2.39, p ˂ 0.001; nine studies). Similar results were observed using hazard ratios (2.36, 95% CI 1.17 to 4.79, p = 0.017; five studies). In six studies, the pooled area under the receiver operating characteristic curve was 0.677 (95% CI 0.612 to 0.743). In our systematic review and meta-analysis, higher De Ritis ratios were significantly associated with severe disease and mortality in COVID-19 patients. Therefore, the De Ritis ratio can be useful for early risk stratification and management in this patient group (PROSPERO registration number: CRD42023406916).
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Affiliation(s)
- Arduino A Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia
- Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Bedford Park, SA 5042, Australia
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
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8
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Liatsos GD. SARS-CoV-2 induced liver injury: Incidence, risk factors, impact on COVID-19 severity and prognosis in different population groups. World J Gastroenterol 2023; 29:2397-2432. [PMID: 37179584 PMCID: PMC10167898 DOI: 10.3748/wjg.v29.i16.2397] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 02/17/2023] [Accepted: 04/07/2023] [Indexed: 04/24/2023] Open
Abstract
Liver is unlikely the key organ driving mortality in coronavirus disease 2019 (COVID-19) however, liver function tests (LFTs) abnormalities are widely observed mostly in moderate and severe cases. According to this review, the overall prevalence of abnormal LFTs in COVID-19 patients ranges from 2.5% to 96.8% worldwide. The geographical variability in the prevalence of underlying diseases is the determinant for the observed discrepancies between East and West. Multifactorial mechanisms are implicated in COVID-19-induced liver injury. Among them, hypercytokinemia with "bystander hepatitis", cytokine storm syndrome with subsequent oxidative stress and endotheliopathy, hypercoagulable state and immuno-thromboinflammation are the most determinant mechanisms leading to tissue injury. Liver hypoxia may also contribute under specific conditions, while direct hepatocyte injury is an emerging mechanism. Except for initially observed severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) tropism for cholangiocytes, more recent cumulative data show SARS-CoV-2 virions within hepatocytes and sinusoidal endothelial cells using electron microscopy (EM). The best evidence for hepatocellular invasion by the virus is the identification of replicating SARS-CoV-2 RNA, S protein RNA and viral nucleocapsid protein within hepatocytes using in-situ hybridization and immunostaining with observed intrahepatic presence of SARS-CoV-2 by EM and by in-situ hybridization. New data mostly derived from imaging findings indicate possible long-term sequelae for the liver months after recovery, suggesting a post-COVID-19 persistent live injury.
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Affiliation(s)
- George D Liatsos
- Department of Internal Medicine, Hippokration General Hospital, Athens 11527, Attiki, Greece
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9
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Anguiano-Albarran R, Cain D, Ashfaq M, Modi A, Gautam S. Multiorgan Failure and Omicron: A Suspected Case of Post-COVID-19 Cholangiopathy. Cureus 2023; 15:e35010. [PMID: 36938182 PMCID: PMC10021348 DOI: 10.7759/cureus.35010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2023] [Indexed: 02/17/2023] Open
Abstract
Since the declaration of a global pandemic by the World Health Organization on March 11, 2020, coronavirus disease 2019 (COVID-19) has impacted millions worldwide. This complex disease process has been primarily associated with respiratory illness. As we continue to learn about COVID-19, there appears to be a growing spectrum of non-pulmonary manifestations. A major topic of interest is hepatic dysfunction related to COVID-19, specifically the growing number of cases involving acute liver failure in the setting of COVID-19. Here, we present a rare case of a patient with COVID-19 antibodies, negative inpatient COVID-19 testing, jaundice, and elusive multiorgan dysfunction.
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Affiliation(s)
- Ricardo Anguiano-Albarran
- Internal Medicine, Texas Christian University School of Medicine - Internal Medicine Residency Program, Fort Worth, USA
| | - Daniel Cain
- Internal Medicine, Texas Christian University School of Medicine - Internal Medicine Residency Program, Fort Worth, USA
| | - Mohammad Ashfaq
- Transplant Hepatology, Baylor Simmons Transplant Institute, Baylor Scott & White All Saints Medical Center, Fort Worth, USA
- Graduate Medical Education, Texas Christian University School of Medicine - Internal Medicine Residency Program, Fort Worth, USA
| | - Apurva Modi
- Transplant Hepatology, Baylor Simmons Transplant Institute, Baylor Scott & White All Saints Medical Center, Fort Worth, USA
- Graduate Medical Education, Texas Christian University School of Medicine - Internal Medicine Residency Program, Fort Worth, USA
| | - Shovendra Gautam
- Graduate Medical Education, Texas Christian University School of Medicine - Internal Medicine Residency Program, Fort Worth, USA
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Peng J, Li F, Wang J, Wang C, Jiang Y, Liu B, He J, Yuan K, Pan C, Lin M, Zhou B, Chen L, Gao D, Zhao Y. Identification of a rare Gli1 + progenitor cell population contributing to liver regeneration during chronic injury. Cell Discov 2022; 8:118. [PMID: 36316325 PMCID: PMC9622734 DOI: 10.1038/s41421-022-00474-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 09/21/2022] [Indexed: 11/06/2022] Open
Abstract
In adults, hepatocytes are mainly replenished from the existing progenitor pools of hepatocytes and cholangiocytes during chronic liver injury. However, it is unclear whether other cell types in addition to classical hepatocytes and cholangiocytes contribute to hepatocyte regeneration after chronic liver injuries. Here, we identified a new biphenotypic cell population that contributes to hepatocyte regeneration during chronic liver injuries. We found that a cell population expressed Gli1 and EpCAM (EpCAM+Gli1+), which was further characterized with both epithelial and mesenchymal identities by single-cell RNA sequencing. Genetic lineage tracing using dual recombinases revealed that Gli1+ nonhepatocyte cell population could generate hepatocytes after chronic liver injury. EpCAM+Gli1+ cells exhibited a greater capacity for organoid formation with functional hepatocytes in vitro and liver regeneration upon transplantation in vivo. Collectively, these findings demonstrate that EpCAM+Gli1+ cells can serve as a new source of liver progenitor cells and contribute to liver repair and regeneration.
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Affiliation(s)
- Jiayin Peng
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Fei Li
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Jia Wang
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Chaoxiong Wang
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Yiao Jiang
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Biao Liu
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Juan He
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Kai Yuan
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Chenyu Pan
- grid.24516.340000000123704535Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Moubin Lin
- grid.24516.340000000123704535Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bin Zhou
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Luonan Chen
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Dong Gao
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.9227.e0000000119573309Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Yun Zhao
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.440637.20000 0004 4657 8879School of Life Science and Technology, ShanghaiTech University, Shanghai, China ,grid.410726.60000 0004 1797 8419Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang China
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11
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Abstract
Knowledge on SARS-CoV-2 infection and its resultant COVID-19 in liver diseases has rapidly increased during the pandemic. Hereby, we review COVID-19 liver manifestations and pathophysiological aspects related to SARS-CoV-2 infection in patients without liver disease as well as the impact of COVID-19 in patients with chronic liver disease (CLD), particularly cirrhosis and liver transplantation (LT). SARS-CoV-2 infection has been associated with overt proinflammatory cytokine profile, which probably contributes substantially to the observed early and late liver abnormalities. CLD, particularly decompensated cirrhosis, should be regarded as a risk factor for severe COVID-19 and death. LT was impacted during the pandemic, mainly due to concerns regarding donation and infection in recipients. However, LT did not represent a risk factor per se of worse outcome. Even though scarce, data regarding COVID-19 specific therapy in special populations such as LT recipients seem promising. COVID-19 vaccine-induced immunity seems impaired in CLD and LT recipients, advocating for a revised schedule of vaccine administration in this population.
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Affiliation(s)
- Jean-François Dufour
- Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Thomas Marjot
- Oxford Liver Unit, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
- Nuffield Department of Medicine, Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Chiara Becchetti
- Department of Hepatology and Gastroenterology, ASST Grande Ospedale Metropolitano Niguarda, Bern, Italy
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
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12
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Richards A, Friesen M, Khalil A, Barrasa MI, Gehrke L, Jaenisch R. SARS-CoV-2 infection of human pluripotent stem cell-derived liver organoids reveals potential mechanisms of liver pathology. iScience 2022; 25:105146. [PMID: 36128218 PMCID: PMC9477603 DOI: 10.1016/j.isci.2022.105146] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 07/25/2022] [Accepted: 09/12/2022] [Indexed: 11/21/2022] Open
Abstract
Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infection can also damage other organs, including the brain, gut, and liver. Symptoms of liver damage are observed in nearly half of patients that succumb to severe SARS-CoV-2 infection. Here we use human-induced pluripotent stem cell-derived liver organoids (HLOs) to recapitulate and characterize liver pathology following virus exposure. Utilizing single-cell sequencing technology, we identified robust transcriptomic changes that occur in SARS-CoV-2 infected liver cells as well as uninfected bystander cells. Our results show a significant induction of many inflammatory pathways, including IFN-α, INF-γ, and IL-6 signaling. Our results further identify IL-6 signaling as a potential mechanism for liver-mediated activation of circulating macrophages.
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Affiliation(s)
- Alexsia Richards
- Whitehead Institute for Biomedical Research, Cambridge, MA 02127, USA
| | - Max Friesen
- Whitehead Institute for Biomedical Research, Cambridge, MA 02127, USA
| | - Andrew Khalil
- Whitehead Institute for Biomedical Research, Cambridge, MA 02127, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
| | | | - Lee Gehrke
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02127, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02127, USA
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, MA 02127, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02127, USA
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13
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Dynamics of hepatocyte-cholangiocyte cell-fate decisions during liver development and regeneration. iScience 2022; 25:104955. [PMID: 36060070 PMCID: PMC9437857 DOI: 10.1016/j.isci.2022.104955] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/17/2022] [Accepted: 08/12/2022] [Indexed: 11/25/2022] Open
Abstract
The immense regenerative potential of the liver is attributed to the ability of its two key cell types – hepatocytes and cholangiocytes – to trans-differentiate to one another either directly or through intermediate progenitor states. However, the dynamic features of decision-making between these cell-fates during liver development and regeneration remains elusive. Here, we identify a core gene regulatory network comprising c/EBPα, TGFBR2, and SOX9 which is multistable in nature, enabling three distinct cell states – hepatocytes, cholangiocytes, and liver progenitor cells (hepatoblasts/oval cells) – and stochastic switching among them. Predicted expression signature for these three states are validated through multiple bulk and single-cell transcriptomic datasets collected across developmental stages and injury-induced liver repair. This network can also explain the experimentally observed spatial organization of phenotypes in liver parenchyma and predict strategies for efficient cellular reprogramming. Our analysis elucidates how the emergent dynamics of underlying regulatory networks drive diverse cell-fate decisions in liver development and regeneration.
Identified minimal regulatory network to model liver development and regeneration Changes in phenotypic landscapes by in-silico perturbations of regulatory networks Ability to explain physiological spatial patterning of liver cell types Decoded strategies for efficient reprogramming among liver cell phenotypes
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14
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El-Sayed Moustafa JS, Jackson AU, Brotman SM, Guan L, Villicaña S, Roberts AL, Zito A, Bonnycastle L, Erdos MR, Narisu N, Stringham HM, Welch R, Yan T, Lakka T, Parker S, Tuomilehto J, Seow J, Graham C, Huettner I, Acors S, Kouphou N, Wadge S, Duncan EL, Steves CJ, Doores KJ, Malim MH, Collins FS, Pajukanta P, Boehnke M, Koistinen HA, Laakso M, Falchi M, Bell JT, Scott LJ, Mohlke KL, Small KS. ACE2 expression in adipose tissue is associated with cardio-metabolic risk factors and cell type composition-implications for COVID-19. Int J Obes (Lond) 2022; 46:1478-1486. [PMID: 35589964 PMCID: PMC9119844 DOI: 10.1038/s41366-022-01136-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 04/21/2022] [Accepted: 04/28/2022] [Indexed: 01/14/2023]
Abstract
BACKGROUND COVID-19 severity varies widely. Although some demographic and cardio-metabolic factors, including age and obesity, are associated with increasing risk of severe illness, the underlying mechanism(s) are uncertain. SUBJECTS/METHODS In a meta-analysis of three independent studies of 1471 participants in total, we investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), measured by RNA-Seq, which acts as a receptor for SARS-CoV-2 cellular entry. RESULTS Lower adipose tissue ACE2 expression was associated with multiple adverse cardio-metabolic health indices, including type 2 diabetes (T2D) (P = 9.14 × 10-6), obesity status (P = 4.81 × 10-5), higher serum fasting insulin (P = 5.32 × 10-4), BMI (P = 3.94 × 10-4), and lower serum HDL levels (P = 1.92 × 10-7). ACE2 expression was also associated with estimated proportions of cell types in adipose tissue: lower expression was associated with a lower proportion of microvascular endothelial cells (P = 4.25 × 10-4) and higher proportion of macrophages (P = 2.74 × 10-5). Despite an estimated heritability of 32%, we did not identify any proximal or distal expression quantitative trait loci (eQTLs) associated with adipose tissue ACE2 expression. CONCLUSIONS Our results demonstrate that individuals with cardio-metabolic features known to increase risk of severe COVID-19 have lower background ACE2 levels in this highly relevant tissue. Reduced adipose tissue ACE2 expression may contribute to the pathophysiology of cardio-metabolic diseases, as well as the associated increased risk of severe COVID-19.
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Affiliation(s)
| | - Anne U Jackson
- Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Sarah M Brotman
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Li Guan
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Sergio Villicaña
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Amy L Roberts
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Antonino Zito
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Genetics, Harvard Medical School, Boston, MA, 02114, USA
| | - Lori Bonnycastle
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michael R Erdos
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Narisu Narisu
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Heather M Stringham
- Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Ryan Welch
- Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Tingfen Yan
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Timo Lakka
- Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio, Finland
- Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland
| | - Stephen Parker
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Jaakko Tuomilehto
- University of Helsinki and Department of Medicine, Helsinki University Hospital, Helsinki, Finland
- Department of Public Health, University of Helsinki, Helsinki, Finland
- Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jeffrey Seow
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Carl Graham
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Isabella Huettner
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Sam Acors
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Neophytos Kouphou
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Samuel Wadge
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Emma L Duncan
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Claire J Steves
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Katie J Doores
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Michael H Malim
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Francis S Collins
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Päivi Pajukanta
- Department of Human Genetics and Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Heikki A Koistinen
- University of Helsinki and Department of Medicine, Helsinki University Hospital, Helsinki, Finland
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Markku Laakso
- Department of Medicine, University of Eastern Finland, Kuopio, Finland
- Kuopio University Hospital, Kuopio, Finland
| | - Mario Falchi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Jordana T Bell
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Laura J Scott
- Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Karen L Mohlke
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Kerrin S Small
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
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15
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Chen H, Chen Q. COVID-19 Pandemic: Insights into Interactions between SARS-CoV-2 Infection and MAFLD. Int J Biol Sci 2022; 18:4756-4767. [PMID: 35874945 PMCID: PMC9305262 DOI: 10.7150/ijbs.72461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/23/2022] [Indexed: 01/08/2023] Open
Abstract
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an ongoing global health pandemic. Since 2019, the pandemic continues to cast a long shadow on all aspects of our lives, bringing huge health and economic burdens to all societies. With our in-depth understanding of COVID-19, from the initial respiratory tract to the later gastrointestinal tract and cardiovascular systems, the multiorgan involvement of this infectious disease has been discovered. Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named nonalcoholic fatty liver disease (NAFLD), is a major health issue closely related to metabolic dysfunctions, affecting a quarter of the world's adult population. The association of COVID-19 with MAFLD has received increasing attention, as MAFLD is a potential risk factor for SARS-CoV-2 infection and severe COVID-19 symptoms. In this review, we provide an update on the interactions between COVID-19 and MAFLD and its underlying mechanisms.
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Affiliation(s)
- Hanfei Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.,Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Qiang Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.,Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.,MOE Frontier Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China
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16
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Elnaggar M, Abomhya A, Elkhattib I, Dawoud N, Doshi R. COVID-19 and liver diseases, what we know so far. World J Clin Cases 2022; 10:3969-3980. [PMID: 35665122 PMCID: PMC9131221 DOI: 10.12998/wjcc.v10.i13.3969] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/15/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) pneumonia outbreak started in December 2019. On March 12, 2020, the World Health Organization (WHO) declared that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitutes a pandemic, and as of May 2021, SARS-CoV-2 has infected over 167.3 million patients, including 3.4 million deaths, reported to WHO. In this review, we will focus on the relationship between SARS-CoV-2 infection and the liver. We will discuss how chronic liver diseases affect the COVID-19 disease course and outcomes. We will also discuss the SARS-CoV-2 effects on the liver, mechanisms of acute liver injury, and potential management plans.
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Affiliation(s)
- Mohamed Elnaggar
- Department of Internal Medicine, University of Nevada Reno School of Medicine, Reno, NV 89052, United States
| | - Ahmed Abomhya
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11200, United States
| | - Ismail Elkhattib
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06030, United States
| | - Nabila Dawoud
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40508, United States
| | - Rajkumar Doshi
- Department of Cardiology, St Joseph's University Medical Center, Paterson, NJ 07503, United States
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17
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Abstract
With the spread of coronavirus disease 2019 (COVID-19) worldwide, extrapulmonary lesions, including liver dysfunction, have attracted growing attention. The mechanisms underlying liver dysfunction in COVID-19 remain unclear. The reported prevalence of liver dysfunction varies widely across studies. In addition, its impact on clinical outcomes and its recovery after discharge are still controversial. In this review, pathological and laboratory findings were analyzed to reveal the potential mechanisms of COVID-19-induced liver injury from onset to recovery. Four patterns of liver damage were summarized according to the pathological findings, including hypoxemia and shock changes, vascular thrombosis and vascular damage, bile duct damage, and other histological changes. With a strict definition, the prevalence of liver dysfunction was not as high as reported. Meanwhile, liver dysfunction improved during the process of recovery. Nevertheless, the definite liver dysfunction was significantly associated with severe clinical course, which should not be ignored.
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Affiliation(s)
- Wen-Zheng Yuan
- Department of Gastrointestinal Surgery II, Renmin Hospital, Wuhan University, Wuhan, Hubei Province, China
| | - Tao Fu
- Department of Gastrointestinal Surgery II, Renmin Hospital, Wuhan University, Wuhan, Hubei Province, China
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18
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Challa SR, Oskrochi G, Chirumamilla LG, Shayegh N, Brim H, Ashktorab H. Predictors of Mortality in Hospitalized African American Covid-19 Cancer Patients. RESEARCH SQUARE 2022:rs.3.rs-1363151. [PMID: 35350203 PMCID: PMC8963688 DOI: 10.21203/rs.3.rs-1363151/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Background Coronavirus disease 2019 (COVID-19) and associated outcomes manifest differently depending on patients' background and pre-existing conditions. It remains unclear how African Americans with and without cancer have been affected. Aim To determine epidemiological, clinical comorbidities, and laboratory test results to identify markers associated with mortality in COVID-19 cancer patients. Methods We reviewed all Covid-19 hospitalized patients records from Dec. 2019 to Oct. 2021 at Howard University Hospital. Patients having a history of, or active cancer status were reviewed. All the clinical, treatment, lab values, and pathological data were extracted. Statical analysis of the Covid-19 cancer patients and comparison with non-cancer Covid-19 patients was performed using univariate and multivariate analyses. Results Out of 512 COVID-19 infected patients, a total of 49 patients were identified with different types of cancer, with both active and previous history. Females consisted of 26 cancer patients (53%). African American race was predominant in both cases and controls, 83.6% and 66.7% respectively. Cancer patients were older than non-cancer patients (Mean Age-70.6 vs. 56.3 years) and had an increased length of hospital stay (Mean 13.9 vs 9.4 days). Among cancer patients, breast cancer was more prevalent in females and prostate cancer in males, (54% and 52% respectively). Comparison of patients with active vs. previous cancer showed no significant difference in the clinical outcome, death vs. discharge (P=0.34). A higher reduction in albumin level in cancer cases, from the time of admission to day five, was significantly associated with death during the same hospital stay compared to those discharged (n=24, 48.9%, p<0.001). In controls, Lymphopenia (n=436, 94.1%, p=0.05), AST (n=59, 12%, p=0.008) and Albumin (n=40, 10.7%, p=0.02) have shown an association with increased mortality. Conclusion Albumin level has shown to have an inverse relationship with clinical outcomes among all COVID infected African American patients. Reduction in Albumin level during the hospital stay, particularly in COVID-19 cancer patients should be considered as a predictor of mortality. No significant difference was noticed in the clinical outcome in patients with previous versus active cancer. Further research with a large cohort size is needed to verify and identify other predictors of outcome in Covid-19 cancer patients and develop appropriate treatment modalities.
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19
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Tian S, Zheng N, Zu X, Wu G, Zhong J, Zhang J, Sheng L, Liu W, Wang C, Ge G, Han J, Zhao J, Li H, Zhang W. Integrated hepatic single-cell RNA sequencing and untargeted metabolomics reveals the immune and metabolic modulation of Qing-Fei-Pai-Du decoction in mice with coronavirus-induced pneumonia. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 97:153922. [PMID: 35032732 PMCID: PMC8720382 DOI: 10.1016/j.phymed.2021.153922] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/24/2021] [Accepted: 12/30/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Although Qing-Fei-Pai-Du decoction (QFPDD) is extensively used clinically to treat COVID-19 patients, the mechanism by which it modulates the immunological and metabolic functions of liver tissue remains unknown. PURPOSE The purpose of this study is to investigate the mechanism of action of QFPDD in the treatment of mice with coronavirus-induced pneumonia by combining integrated hepatic single-cell RNA sequencing and untargeted metabolomics. METHODS We developed a human coronavirus pneumonia model in BALB/c mice by infecting them with human coronavirus HCoV-229E with stimulating them with cold-damp environment. We initially assessed the status of inflammation and immunity in model mice treated with or without QFPDD by detecting peripheral blood lymphocytes and inflammatory cytokines. Then, single-cell RNA sequencing and untargeted metabolomics were performed on mouse liver tissue. RESULTS HCoV-229E infection in combination with exposure to a cold-damp environment significantly decreased the percentage of peripheral blood lymphocytes (CD4+ and CD8+ T cells, B cells) in mice, which was enhanced by QFPDD therapy. Meanwhile, the levels of inflammatory cytokines such as IL-6, TNF-α, and IFN-γ were significantly increased in mouse models but significantly decreased by QFPDD treatment. Single-cell RNA sequencing analysis showed that QFPDD could attenuate disease-associated alterations in gene expression, core transcriptional regulatory networks, and cell-type composition. Computational predictions indicated that QFPDD rectified the observed aberrant patterns of cell-cell communication. Additionally, the metabolic profiles of liver tissue in the Model group were distinct from mice in the Control group, and QFPDD significantly regulated hepatic purine metabolism. CONCLUSION To the best of our knowledge, this study is the first to integrate hepatic single-cell RNA sequencing and untargeted metabolomics into a TCM formula and these valuable findings indicate that QFPDD can improve immune function and reduce liver injury and inflammation.
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Affiliation(s)
- Saisai Tian
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Ningning Zheng
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xianpeng Zu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Gaosong Wu
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jing Zhong
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou 313000, China
| | - Jinbo Zhang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Department of Pharmacy, Tianjin Rehabilitation and Recuperation Center, Joint Logistics Support Force, Tianjin, China
| | - Lili Sheng
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Chaoran Wang
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Guangbo Ge
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jingyan Han
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Jing Zhao
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Houkai Li
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Weidong Zhang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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20
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Alibeik N, Pishgar E, Bozorgmehr R, Aghaaliakbari F, Rahimian N. Potential role of gut microbiota in patients with COVID-19, its relationship with lung axis, central nervous system (CNS) axis, and improvement with probiotic therapy. IRANIAN JOURNAL OF MICROBIOLOGY 2022; 14:1-9. [PMID: 35611351 PMCID: PMC9085538 DOI: 10.18502/ijm.v14i1.8794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Coronavirus Disease 2019 (COVID-19) is a pandemic disease caused by a new corona virus. COVID-19 affects different people in different ways. COVID-19 could affect the gastrointestinal system via gut microbiota impairment. Gut microbiota could affect lung health through a relationship between gut and lung microbiota, which is named gut-lung axis. Gut microbiota impairment plays a role in pathogenesis of various pulmonary disease states, so GI diseases were found to be associated with respiratory diseases. Moreover, most infected people will develop mild to moderate gastrointestinal (GI) symptoms such as diarrhea, vomiting, and stomachache, which is caused by impairment in gut microbiota. Therefore, the current study aimed to review potential role of gut microbiota in patients with COVID-19, its relation with lung axis, Central Nervous System (CNS) axis and improvement with probiotic therapy. Also, this review can be a guide for potential role of gut microbiota in patients with COVID-19.
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Affiliation(s)
- Nazanin Alibeik
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Elham Pishgar
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ramin Bozorgmehr
- Department of Surgery, School of Medicine, Shahid Madani Hospital, Alborz University of Medical Sciences, Karaj, Iran
| | - Farshad Aghaaliakbari
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Neda Rahimian
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
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21
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Verma HK, Bhaskar LVKS. SARS-CoV-2 infection in people with pre-existing liver disease: Further research is warranted. World J Gastroenterol 2021; 27:7855-7858. [PMID: 34963747 PMCID: PMC8661380 DOI: 10.3748/wjg.v27.i45.7855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/13/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with severe liver disease who have been infected with severe acute respiratory syndrome coronavirus-2 (coronavirus disease 2019) frequently develop acute respiratory distress syndrome and multiple organ failure, with a high mortality rate, as a result of the hyper-proinflammatory state known as the cytokine storm. Clinicians must recognize cytokine storms earlier to avoid intensive care admission and multi-organ damage, a critical life-threatening condition with prognostic and therapeutic implications.
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Affiliation(s)
- Henu Kumar Verma
- Department of Immunopathology, Institute of lungs Biology and Disease, Comprehensive Pneumology Center, Neuherberg 85764, Munich, Germany
| | - LVKS Bhaskar
- Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495001, Chhattisgarh, India
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22
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Sun H, Chen Q, Liu W, Liu Y, Ruan S, Zhu C, Ruan Y, Ying S, Lin P. TROP2 modulates the progression in papillary thyroid carcinoma. J Cancer 2021; 12:6883-6893. [PMID: 34659576 PMCID: PMC8518010 DOI: 10.7150/jca.62461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/18/2021] [Indexed: 12/18/2022] Open
Abstract
Background: Tumor-associated calcium signal transducer 2 (TROP2) is over expressed in various kinds of human cancers and plays important roles in the proliferation, invasion and metastasis of tumor cells. However, the expression and molecular mechanism of TROP2 in thyroid papillary carcinoma (PTC) are unclear. Methods: The expressions of TROP2 in PTC and control tissue were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The proliferation and invasion of PTC cell lines were examined by cell cloning and transwell assays. RNA sequencing analysis and public data analysis were assessed to investigate the potential mechanisms of TROP2 in PTC. Gene correlation analysis was conducted to explore the association between TROP2 and the related gene ISG15 in patients with PTC. Results: The expression of TROP2 was significantly higher in PTC than control. The high expression of TROP2 protein was associated with lymph node metastasis, tumor size and capsular infiltration (P<0.05). SiRNA-mediated TROP2 gene expression silencing can significantly inhibit proliferation and migration of PTC cells. ISG15 decreased in TROP2 siRNA PTC cells and increased in PTC patients significantly. There was a significant correlation between the expression of TROP2 and ISG15 in PTC patients. TROP2 interacted directly with ATP6V1A, CEBPA and SOX5 and then further interacted with the immune genes. TROP2 expression and tumor-infiltrating immune cells were also correlated in thyroid cancer microenvironment. Conclusions: TROP2 promotes the development of PTC. TROP2 expression was correlated with ISG15 and tumor-infiltrating immune cells in thyroid cancer.
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Affiliation(s)
- Huali Sun
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Qi Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Weiping Liu
- Nuclear Medicine Department, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Yanmei Liu
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Sihan Ruan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Chumeng Zhu
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Yanyun Ruan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Shenpeng Ying
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Peipei Lin
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
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23
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Rad H, Röhl J, Stylianou N, Allenby M, Bazaz S, Warkiani ME, Guimaraes FSF, Clifton VL, Kulasinghe A. The Effects of COVID-19 on the Placenta During Pregnancy. Front Immunol 2021; 12:743022. [PMID: 34603330 PMCID: PMC8479199 DOI: 10.3389/fimmu.2021.743022] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 08/26/2021] [Indexed: 12/21/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The virus primarily affects the lungs where it induces respiratory distress syndrome ranging from mild to acute, however, there is a growing body of evidence supporting its negative effects on other system organs that also carry the ACE2 receptor, such as the placenta. The majority of newborns delivered from SARS-CoV-2 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. There appears to be a higher incidence of pregnancy-related complications in SARS-CoV-2 positive mothers, such as miscarriage, restricted fetal growth, or still-birth. In this review, we discuss the pathobiology of COVID-19 maternal infection and the potential adverse effects associated with viral infection, and the possibility of transplacental transmission.
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Affiliation(s)
- Habib Sadeghi Rad
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Joan Röhl
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Nataly Stylianou
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Mark C. Allenby
- School of Chemical Engineering, University of Queensland, St Lucia, QLD, Australia
- Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, QLD, Australia
| | - Sajad Razavi Bazaz
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
| | - Majid E. Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
| | | | - Vicki L. Clifton
- Mater Research Institute, University of Queensland, Brisbane, QLD, Australia
| | - Arutha Kulasinghe
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
- The University of Queensland Diamantina Institute (UQDI), Brisbane, QLD, Australia
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24
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Sun H, Chen Q, Liu W, Liu Y, Ruan S, Zhu C, Ruan Y, Ying S, Lin P. TROP2 modulates the progression in papillary thyroid carcinoma. J Cancer 2021; 12. [PMID: 34659576 PMCID: PMC8518010 DOI: 10.7150/jca.62461&set/a 833480617+850328715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Background: Tumor-associated calcium signal transducer 2 (TROP2) is over expressed in various kinds of human cancers and plays important roles in the proliferation, invasion and metastasis of tumor cells. However, the expression and molecular mechanism of TROP2 in thyroid papillary carcinoma (PTC) are unclear. Methods: The expressions of TROP2 in PTC and control tissue were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The proliferation and invasion of PTC cell lines were examined by cell cloning and transwell assays. RNA sequencing analysis and public data analysis were assessed to investigate the potential mechanisms of TROP2 in PTC. Gene correlation analysis was conducted to explore the association between TROP2 and the related gene ISG15 in patients with PTC. Results: The expression of TROP2 was significantly higher in PTC than control. The high expression of TROP2 protein was associated with lymph node metastasis, tumor size and capsular infiltration (P<0.05). SiRNA-mediated TROP2 gene expression silencing can significantly inhibit proliferation and migration of PTC cells. ISG15 decreased in TROP2 siRNA PTC cells and increased in PTC patients significantly. There was a significant correlation between the expression of TROP2 and ISG15 in PTC patients. TROP2 interacted directly with ATP6V1A, CEBPA and SOX5 and then further interacted with the immune genes. TROP2 expression and tumor-infiltrating immune cells were also correlated in thyroid cancer microenvironment. Conclusions: TROP2 promotes the development of PTC. TROP2 expression was correlated with ISG15 and tumor-infiltrating immune cells in thyroid cancer.
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Affiliation(s)
- Huali Sun
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Qi Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Weiping Liu
- Nuclear Medicine Department, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Yanmei Liu
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Sihan Ruan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Chumeng Zhu
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Yanyun Ruan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Shenpeng Ying
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
| | - Peipei Lin
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, P. R. China
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