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11 pages, 948 KiB

Open AccessArticle

HDV RNA Levels and Progression of Hepatitis Delta Infection: A 14 Year Follow Up Experience in Italy

by Alessandra Mangia, Maria Maddalena Squillante, Filippo Fraticelli, Maria Chiara Cavorsi, Giulia Paroni, Lucia Zaffarano and Annarita Valeria Piazzolla

Cells 2023, 12(10), 1413; https://doi.org/10.3390/cells12101413 - 17 May 2023

Cited by 4 | Viewed by 1871

Abstract

Background: Identification of outcome predictors is one of the unmet needs in chronic HDV infection. Until recently, no reliable quantitative assays for HDV RNA were available. Aims: To evaluate the impact of baseline viremia on natural history of HDV infection in a cohort [...] Read more.

Background: Identification of outcome predictors is one of the unmet needs in chronic HDV infection. Until recently, no reliable quantitative assays for HDV RNA were available. Aims: To evaluate the impact of baseline viremia on natural history of HDV infection in a cohort of patients whose serum samples were stored at their first visit 15 years ago. Methods: Quantitative HBsAg, HBeAg, HBeAb, HBV DNA, HDV RNA, genotypes, and liver disease severity were assessed at baseline. Patients who were no longer on active follow-up were recalled and re-evaluated in August 2022. Results: The majority of patients were male (64.9%); the median age was 50.1 years; and all patients were Italian, with only three born in Romania. All were HBeAg negative with HBV genotype D infection. Patients were subdivided three groups: 23 were in active follow-up (Group 1), 21 were recalled due to no longer being in follow-up (Group 2), and 11 died (Group 3). Liver cirrhosis was diagnosed in 28 subjects at the first visit; 39.3% of diagnosed patients were in Group 3, 32.1% were in Group 1 and 28.6% were in Group 2 (p = 0.001). Baseline HBV DNA IU/mL Log10 were 1.6 (1.0–5.9) in Group 1, 1.3 (1.0–4.5) in Group 2, and 4.1 (1.5–4.5) in Group 3; median baseline HDV RNA Log10 levels were 4.1 (0.7–6.7) in Group 1, 3.2 (0.7–6.2) in Group 2, and 5.2 (0.7–6.7) in Group 3, resulting significantly higher rates among patients in Group 3 compared to the other groups (p = 0.038). Eighteen patients in Group 2, as compared to 7 in Group 1, had undetectable HDV RNA at the follow-up evaluation (p = 0.001). Conclusions: HDV chronic infection is a heterogeneous disease. It may not only progress but also improve over time in patients, who eventually become HDV RNA-undetectable. HDV RNA levels may help identify the subgroup of patients with less progressive liver disease. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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15 pages, 1491 KiB

Open AccessArticle

Focal Liver Lesion MRI Feature Identification Using Efficientnet and MONAI: A Feasibility Study

by Róbert Stollmayer, Bettina Katalin Budai, Aladár Rónaszéki, Zita Zsombor, Ildikó Kalina, Erika Hartmann, Gábor Tóth, Péter Szoldán, Viktor Bérczi, Pál Maurovich-Horvat and Pál Novák Kaposi

Cells 2022, 11(9), 1558; https://doi.org/10.3390/cells11091558 - 5 May 2022

Cited by 6 | Viewed by 3294

Abstract

Liver tumors constitute a major part of the global disease burden, often making regular imaging follow-up necessary. Recently, deep learning (DL) has increasingly been applied in this research area. How these methods could facilitate report writing is still a question, which our study [...] Read more.

Liver tumors constitute a major part of the global disease burden, often making regular imaging follow-up necessary. Recently, deep learning (DL) has increasingly been applied in this research area. How these methods could facilitate report writing is still a question, which our study aims to address by assessing multiple DL methods using the Medical Open Network for Artificial Intelligence (MONAI) framework, which may provide clinicians with preliminary information about a given liver lesion. For this purpose, we collected 2274 three-dimensional images of lesions, which we cropped from gadoxetate disodium enhanced T1w, native T1w, and T2w magnetic resonance imaging (MRI) scans. After we performed training and validation using 202 and 65 lesions, we selected the best performing model to predict features of lesions from our in-house test dataset containing 112 lesions. The model (EfficientNetB0) predicted 10 features in the test set with an average area under the receiver operating characteristic curve (standard deviation), sensitivity, specificity, negative predictive value, positive predictive value of 0.84 (0.1), 0.78 (0.14), 0.86 (0.08), 0.89 (0.08) and 0.71 (0.17), respectively. These results suggest that AI methods may assist less experienced residents or radiologists in liver MRI reporting of focal liver lesions. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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14 pages, 8623 KiB

Open AccessArticle

Optimized Isolation and Characterization of C57BL/6 Mouse Hepatic Stellate Cells

by Alexandre Balaphas, Jeremy Meyer, Cécile Gameiro, Aurélien Frobert, Marie-Noëlle Giraud, Bernhard Egger, Leo H. Bühler and Carmen Gonelle-Gispert

Cells 2022, 11(9), 1379; https://doi.org/10.3390/cells11091379 - 19 Apr 2022

Cited by 3 | Viewed by 4716

Abstract

To obtain meaningful results of hepatic stellate cell (HSC) function, it is crucial to use highly pure HSC populations. Our aim was to optimize HSC isolation from mice livers without exploiting the characteristically transient vitamin A autofluorescence of HSC. HSCs were isolated from [...] Read more.

To obtain meaningful results of hepatic stellate cell (HSC) function, it is crucial to use highly pure HSC populations. Our aim was to optimize HSC isolation from mice livers without exploiting the characteristically transient vitamin A autofluorescence of HSC. HSCs were isolated from C57BL/6 mice using a two-step collagenase digestion and Nycodenz gradient separation followed by CD11b-negative sorting step in order to remove contaminating macrophages and dendritic cells. Isolated cells were analyzed for yield, viability, purity, and potential new markers using immunofluorescence and flow cytometry. We obtained a yield of 350,595 ± 100,773 HSC per mouse liver and a viability of isolated cells of 92.4 ± 3.1%. We observed a low macrophage/dendritic cell contamination of 1.22 ± 0.54%. Using flow cytometry, we demonstrated that CD38 was expressed at the surface of HSC subpopulations and that all expressed intracellular markers specific for HSC in the liver. This isolation method, avoiding fluorescent activated cell sorting (FACS), allowed isolation of HSCs with high purity. Further, flow cytometry analysis suggests that CD38 may be a reliable marker of HSCs and may include subpopulations of HSCs without retinoid droplets. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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14 pages, 6065 KiB

Open AccessArticle

PROX1, a Key Mediator of the Anti-Proliferative Effect of Rapamycin on Hepatocellular Carcinoma Cells

by Sora Kwon, Kiwon Ban, Young-Kwon Hong, Jung-Suk Sung and Inho Choi

Cells 2022, 11(3), 446; https://doi.org/10.3390/cells11030446 - 27 Jan 2022

Cited by 3 | Viewed by 3452

Abstract

The MTOR signal is known to be activated in various cancer cells including hepatocellular carcinoma (HCC) cells. Rapamycin, a specific inhibitor of MTOR, has been widely used as an immunosuppressant in organ transplant patients, and its clinical application has been recently expanded to [...] Read more.

The MTOR signal is known to be activated in various cancer cells including hepatocellular carcinoma (HCC) cells. Rapamycin, a specific inhibitor of MTOR, has been widely used as an immunosuppressant in organ transplant patients, and its clinical application has been recently expanded to cancer therapy. In this study, the anti-proliferative effect of rapamycin was investigated in four different HCC cell lines. Rapamycin effectively inhibited the proliferation of Huh7 or Hep3B, but not that of HepG2 or SNU3160 cells. Interestingly, rapamycin increased Prospero-related homeobox 1 (PROX1) expression at the protein level, but did not affect its transcript in Huh7 as well as Hep3B cells. Moreover, immunoprecipitation assays showed that PROX1 ubiquitination was downregulated by rapamycin. Furthermore, PROX1 over-expression or siRNA knock-down in Huh7 and Hep3B cells reduced or increased proliferation, respectively. The effect of PROX1 over-expression on the sensitivity to rapamycin was not synergistic, but the effect of MTOR inhibition on cell proliferation was diminished by PROX1 siRNA. Finally, Huh7 cells were inoculated into the flanks of nude mice and rapamycin was injected daily for 14 days. The xenograft volume was decreased and PROX1 expression was increased by rapamycin. These results indicate that PROX1 plays a key role in the anti-proliferative effect of rapamycin and suggest that the increased PROX1 by MTOR inhibition can be used as a useful marker for predicting whether HCC cells can be affected by rapamycin. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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19 pages, 31525 KiB

Open AccessArticle

Deficiency of Cathelicidin Attenuates High-Fat Diet Plus Alcohol-Induced Liver Injury through FGF21/Adiponectin Regulation

by Fengyuan Li, Jenny Chen, Yunhuan Liu, Zelin Gu, Mengwei Jiang, Lihua Zhang, Shao-Yu Chen, Zhongbin Deng, Craig J. McClain and Wenke Feng

Cells 2021, 10(12), 3333; https://doi.org/10.3390/cells10123333 - 27 Nov 2021

Cited by 9 | Viewed by 3266

Abstract

Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide—gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and [...] Read more.

Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide—gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and steatosis in WT mice, which were attenuated in Camp^–/– mice. Neutrophil infiltration was lessened in the liver of Camp^–/– mice. HFDE feeding dramatically increased epididymal white adipose tissue (eWAT) mass and induced adipocyte hypertrophy in WT mice, whereas these effects were attenuated by the deletion of Camp. Furthermore, Camp^–/– mice had significantly increased eWAT lipolysis, evidenced by up-regulated expression of lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). The depletion of Camp also increased uncoupling protein 1 (UCP1)-dependent thermogenesis in the brown adipose tissue (BAT) of mice. HFDE fed Camp^–/– mice had elevated protein levels of fibroblast growth factor 21 (FGF21) in the eWAT, with an increased adiponectin production, which had been shown to alleviate hepatic fat deposition and inflammation. Collectively, we have demonstrated that Camp^–/– mice are protected against HFD plus alcohol-induced liver injury and steatosis through FGF21/adiponectin regulation. Targeting CRAMP could be an effective approach for prevention/treatment of high-fat diet plus alcohol consumption-induced steatohepatitis. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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Review

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7 pages, 568 KiB

Open AccessReview

Treatment of Chronic Hepatitis D with Bulevirtide—A Fight against Two Foes—An Update

by Peter Ferenci, Thomas Reiberger and Mathias Jachs

Cells 2022, 11(22), 3531; https://doi.org/10.3390/cells11223531 - 8 Nov 2022

Cited by 12 | Viewed by 3077

Abstract

HDV infection frequently causes progression to cirrhosis and hepatocellular carcinoma (HCC). In summer 2020, the first potentially effective drug Bulevirtide (BLV) has been approved for the treatment of HDV by the EMA. BLV is a synthetic N-acylated pre-S1 lipopeptide that blocks the binding [...] Read more.

HDV infection frequently causes progression to cirrhosis and hepatocellular carcinoma (HCC). In summer 2020, the first potentially effective drug Bulevirtide (BLV) has been approved for the treatment of HDV by the EMA. BLV is a synthetic N-acylated pre-S1 lipopeptide that blocks the binding of HBsAg-enveloped particles to the sodium taurocholate co-transporting polypeptide (NTCP), which is the cell entry receptor for both HBV and HDV. In this review, we discuss the available data from the ongoing clinical trials and from “real world series”. Clinical trials and real-world experiences demonstrated that BLV 2 mg administered for 24 or 48 weeks as monotherapy or combined with pegIFNα reduces HDV viremia and normalizes ALT levels in a large proportion of patients. The combination of BLV and pegIFNα shows a synergistic on-treatment effect compared with either one of the monotherapies. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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20 pages, 2234 KiB

Open AccessReview

mRNA-Based Approaches to Treating Liver Diseases

by Maximiliano L. Cacicedo, María José Limeres and Stephan Gehring

Cells 2022, 11(20), 3328; https://doi.org/10.3390/cells11203328 - 21 Oct 2022

Cited by 8 | Viewed by 3535

Abstract

Diseases that affect the liver account for approximately 2 million deaths worldwide each year. The increasing prevalence of these diseases and the limited efficacy of current treatments are expected to stimulate substantial growth in the global market for therapeutics that target the liver. [...] Read more.

Diseases that affect the liver account for approximately 2 million deaths worldwide each year. The increasing prevalence of these diseases and the limited efficacy of current treatments are expected to stimulate substantial growth in the global market for therapeutics that target the liver. Currently, liver transplantation is the only curative option available for many liver diseases. Gene therapy represents a valuable approach to treatment. The liver plays a central role in a myriad of essential metabolic functions, making it an attractive organ for gene therapy; hepatocytes comprise the most relevant target. To date, viral vectors constitute the preferred approach to targeting hepatocytes with genes of therapeutic interest. Alternatively, mRNA-based therapy offers a number of comparative advantages. Clinical and preclinical studies undertaken to treat inherited metabolic diseases affecting the liver, cirrhosis and fibrosis, hepatocellular carcinoma, hepatitis B, and cytomegalovirus using lipid nanoparticle-encapsulated mRNAs that encode the therapeutic or antigenic protein of interest are discussed. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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31 pages, 3615 KiB

Open AccessReview

Recent Advancements in Antifibrotic Therapies for Regression of Liver Fibrosis

by Anshika Jangra, Ashish Kothari, Phulen Sarma, Bikash Medhi, Balram Ji Omar and Karanvir Kaushal

Cells 2022, 11(9), 1500; https://doi.org/10.3390/cells11091500 - 29 Apr 2022

Cited by 23 | Viewed by 5417

Abstract

Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can [...] Read more.

Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can result in inflammation and fibrosis. This activates myofibroblasts to secrete ECM proteins, resulting in the formation of fibrous scars on the liver. Fibrosis regression is possible through the removal of pathophysiological causes as well as the elimination of activated myofibroblasts, resulting in the reabsorption of the scar tissue. To date, a wide range of antifibrotic therapies has been tried and tested, with varying degrees of success. These therapies include the use of growth factors, cytokines, miRNAs, monoclonal antibodies, stem-cell-based approaches, and other approaches that target the ECM. The positive results of preclinical and clinical studies raise the prospect of a viable alternative to liver transplantation in the near future. The present review provides a synopsis of recent antifibrotic treatment modalities for the treatment of liver cirrhosis, as well as a brief summary of clinical trials that have been conducted to date. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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11 pages, 299 KiB

Open AccessReview

Scientific Validation and Clinical Application of Lung Cancer Organoids

by Dahye Lee, Yoonjoo Kim and Chaeuk Chung

Cells 2021, 10(11), 3012; https://doi.org/10.3390/cells10113012 - 4 Nov 2021

Cited by 16 | Viewed by 5163

Abstract

Lung cancer organoid (LCO) is a novel model of lung cancer that facilitates drug screening. However, the success rate of LCOs varies from 7% to 87%, and the culture medium compositions are markedly different. Airway organoid media can be used for LCO cultures, [...] Read more.

Lung cancer organoid (LCO) is a novel model of lung cancer that facilitates drug screening. However, the success rate of LCOs varies from 7% to 87%, and the culture medium compositions are markedly different. Airway organoid media can be used for LCO cultures, but this promotes the overgrowth of normal cell organoids especially in LCOs from intrapulmonary lesions. Several modified media are specifically utilized for promoting the cancer cell’s growth. For culturing high-purity LCOs, cancer cells from metastatic lesions and malignant effusions are used. Recently, single-cell RNA sequencing has identified previously unknown cell populations in the lungs and lung cancer. This sequencing technology can be used to validate whether the LCO recapitulates the heterogeneity and functional hierarchy of the primary tumor. Several groups have attempted to culture LCOs with mesenchymal cells and immune cells to recapitulate the tumor microenvironment. Disease modeling using LCO provides novel insight into the pathophysiology of lung cancer and enables high-throughput screening for drug discovery and prognosis prediction. An LCO model would help to identify new concepts as a basis for lung cancer targeting by discovering innovative therapeutic targets. Full article

(This article belongs to the Special Issue Hepatology: From Natural History to Therapeutics)

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